CN102459158A - Novel amide and amidine derivatives and uses thereof - Google Patents

Novel amide and amidine derivatives and uses thereof Download PDF

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Publication number
CN102459158A
CN102459158A CN2010800264724A CN201080026472A CN102459158A CN 102459158 A CN102459158 A CN 102459158A CN 2010800264724 A CN2010800264724 A CN 2010800264724A CN 201080026472 A CN201080026472 A CN 201080026472A CN 102459158 A CN102459158 A CN 102459158A
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Prior art keywords
methyl
amino
cyanic acid
diamantane
acyl group
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CN2010800264724A
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CN102459158B (en
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S.佩迪
M.V.帕特尔
J.J.罗德
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AbbVie Inc
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Abbott GmbH and Co KG
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Abstract

The present invention relates to inhibitors of 11- ss-hydroxysteroid dehydrogenase type 1 enzyme and their use in treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, central nervous system disorders, and diseases and conditions that are related to excessive glucocorticoids.

Description

New acid amides and amidine derivative and its purposes
The field of the invention
The present invention relates to new acid amides, cyano amidine, thioamides, amidine, hydroxyl imide acid amides, alkoxyl group imines acid amides, aryloxy imines acid amides and relevant compound, it is the 11-beta-hydroxysteroid dehydrogenase 1 type (suppressor factor of enzyme of 11 β-HSD1).The purposes that the suppressor factor that the invention further relates to 11 β-HSD1 enzyme is used to treat at its philtrum of needs.
Background of the present invention
Glucocorticosteroid in blood with activity form (that is, at philtrum with the hydrocortisone form) and inactive form (that is, at philtrum with the Kendall compound form) circulation.Many researchs show, 11 β-HSD1 in vivo and in intact cell, mainly play the reductase enzyme effect.It makes inactive 11-ketone group glucocorticosteroid (promptly; Kendall compound or dehydrocorticosterone) change active 11-hydroxyl glucocorticosteroid into (promptly; Hydrocortisone or Kendall compound), and strengthen the glucocorticosteroid effect with the tissue specificity mode thus, cause the partial concn of hydrocortisone higher.Suppress the tissue specificity enhancing that 11 β-HSD1 could prevent or reduce the glucocorticosteroid effect, and favourable effect is provided thus.
11 β-HSD1 is low affinity enzyme, and it has the K at micro-molar range for Kendall compound m, this scope preferentially is NADPH/NADP +The cofactor of (Triphosphopyridine nucleotide, reduced).11 β-HSD1 expresses in various tissues widely, for example liver, bone, brain, lung, fat and VSMC.
In liver and fatty tissue, over-drastic glucocorticosteroid effect meeting causes insulin resistant, type ii diabetes, and hyperlipemia, increase that the abdomen position is fat and vascular hypertension (people such as Su, Progress in Medicinal Chemistry, 46,29-130 (2008); People such as Webster, Expert Opin. Ther. Patents,17 (12), 1407-1422 (2007); Wang, Drug Discovery Today:Ther. Strategies,4 (2), 117-122 (2007); Link, Current Opin. In Invest. Drugs, 4 (4), 421-429 (2003); People such as Seckl, Endocrinology, 142,1371-1376 (2001) and the reference of wherein quoting).Correspondingly, 11 beta-HSD 1 inhibitors kinds be acknowledged as one of extremely promising treatment kind (Norman P., Insight Pharma Reports,103-110 (April 2007)).
Disclosed data are illustrated in that rising glucocorticosteroid level can cause neuronic sex change and dysfunction in the mammal brain, particularly (de Quervain in the old man Deng the people, Hum Mol Genet., 13,47-52 (2004); Belanoff Et al. J. Psychiatr Res.,35,127-35, (2001)).In the evidence explanation of rodents and philtrum, the long-term rising of blood plasma glucocorticosteroid level can make cognitive function weaken, and this weakening becomes more serious along with aging. (Issa Deng the people, J. Neurosci., 10,3247-3254 (1990); Lupien Et al., Nat. Neurosci., 1,69-73 (1998); Yau Et al., Neuroscience, 66,571-581 (1995)).Long-term excessive cortisol levels in the brain can cause neurone forfeiture and neuron dysfunction.(Kerr Deng the people, Psychobiology, 22,123-133 (1994); Woolley, Brain Res., 531,225-231, (1990); Landfield, Science, 272,1249-1251 (1996)).
In addition, the acute mental disorder that glucocorticosteroid causes has been explained the more pharmacology inducing action of this response, and when with these steroidal pharmaceutical treatments patients, its be the problem mainly considered of doctor (people such as Wolkowitz, Ann NY Acad Sci., 1032,191-194 (2004)).Show recently; 11 β-HSD1 mRNA expresses in people hippocampus, volume side cortex and cerebellum; And, can improve fluency and the memory (people such as Thekkapat of speech with nonselective 11 β-HSD1 and 11 β-HSD2 suppressor factor carbenoxolone treatment sensile diabetic patient Proc Natl Acad Sci USA, 101,6743-6749 (2004)).Excessive glucocorticosteroid level also influences spiritual pathology, and shown in animal model, it causes anxiety and aggressive behaviour to obtain increasing.The long-term rising of hydrocortisone also with the Cushing's disease in melancholia relevant (McEwen, Metab. Clin. & Exp., 54,20-23 (2005)).Many animals and clinical study provide the glucocorticosteroid level improve and the neuropsychiatry illness (for example; The severe depression illness; Psychotic depression, anxiety, Phobias; Melancholia in post-traumatic nervous sexual dysfunction and the Cushing's syndromes) associated evidence (Budziszewska between Polish J. of Pharmacol., 54,343-349, (2002); People such as Str hle, Pharmacopsychiatry,36, S207-S214 (2003); People such as DeBattista, TRENDS in Endocr. Metab.,17,117-120 (2006); People such as Norman, Expert Rev. Neurotherapeutics,7,203-213 (2007)).
Thus, suppressing 11 β-HSD1 can make the patient who suffers from following disease be benefited: non-insulin-dependent type ii diabetes, insulin resistant, obesity; Lipid metabolism disorders, metabolic syndromes, central nervous system disorders, age the decline relevant or cognitive function that glucocorticosteroid is relevant; For example, those seen illnesss in alzheimer's disease and relevant dementia, severe depression illness, psychotic depression; Anxiety, Phobias, post-traumatic nervous sexual dysfunction; Melancholia in the Cushing's syndromes, intractable melancholia reaches other disease and illness that the effect of over-drastic glucocorticosteroid is mediated.
The present invention's general introduction
An embodiment relates to the compound of formula (I)
Figure 488751DEST_PATH_IMAGE001
(I),
Wherein
L is-(CH 2) n-,-(CR 38R 39) m-X-(CR 38R 39) n-or-(CR 38R 39) m-X-(CR 38R 39) n-Y-;
M is 0,1 or 2 when occurring at every turn independently;
N is 0,1 or 2 when occurring at every turn independently;
R 1Be naphthenic base or heterocycle;
R 2Be hydrogen, alkyl or aryl; Or R 1And R 2The atom that is connected with them forms heterocycle; Or R 2And R 3The atom that is connected with them forms heterocycle;
R 3And R 4Be hydrogen independently, alkyl or cycloalkyl; Or R 3And R 4The atom that is connected with them forms naphthenic base, heterocycle, heteroaryl or aryl;
R 5Be hydrogen, alkyl, amino, aryl, naphthenic base, heteroaryl or heterocycle, condition is: when L is-(CR 38R 39) m-X-(CR 38R 39) nDuring-Y-, R 5Not amino; Or R 4And R 5The atom that is connected with them forms naphthenic base or heterocycle;
X is-O-,-S-, and-S (O)-,-S (O) 2-,-NR 36-or-CR 36R 37-;
Y is O or NR 40
R 36And R 37Be hydrogen or alkyl independently when occurring at every turn; Or R 36And R 2The atom that is connected with them forms heterocycle;
R 38, R 39And R 40Be hydrogen or alkyl independently when occurring at every turn;
W is O, N-CN, N-OR 6, N-R 6Or S; With
R 6Be hydrogen, alkyl or aryl; Or
Its pharmacologically acceptable salt, ester, acid amides, N-oxide compound or prodrug.
Another embodiment comprises that formula (I) compound is used to treat the purposes of 11 β-illness that the HSD1 enzyme is mediated, for example, and non-insulin-dependent type ii diabetes, insulin resistant; Obesity, lipid metabolism disorders, metabolic syndromes, age the decline relevant or cognitive function that glucocorticosteroid is relevant; For example, those seen illnesss in alzheimer's disease and relevant dementia, severe depression illness, psychotic depression; Anxiety, Phobias, post-traumatic nervous sexual dysfunction; Melancholia in the Cushing's syndromes, intractable melancholia reaches other disease and illness that the effect of over-drastic glucocorticosteroid is mediated.
Another embodiment relates to pharmaceutical composition, and it comprises the compound and the pharmacy suitable carriers of the formula (I) of treating significant quantity.
Detailed description of the present invention
The definition of term
Once above variable occurs in this article arbitrary substituting group or in The compounds of this invention or any other chemical formula, its definition and its definition when other occurs when at every turn occurring has nothing to do.Substituting group can make up, as long as this combination can produce stable compound.Stable compound is can be with useful purity isolated compound from reaction mixture.
The following term of in this specification sheets and additional claim, using has following meanings:
Term " ethanoyl " is meant-C (O) CH 3Group.
Term " acyl group " is meant the alkyl that is connected with parent molecular moiety through carbonyl defined herein.The representational example of acyl group is including, but not limited to ethanoyl, 1-oxopropyl, 2,2-dimethyl--1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.
Term " acyloxy " is meant the acyl group that is connected with parent molecular moiety through Sauerstoffatom.The representational example of acyloxy is including, but not limited to acetoxyl group, propionyloxy and isobutyryl oxygen base.
Term " thiazolinyl " is meant the straight or branched hydrocarbon that contains 2 to 10 carbon, preferred 2,3,4,5 or 6 carbon, and contain at least one carbon-to-carbon double bond.The representational example of thiazolinyl is including, but not limited to vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-crotonyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl isophthalic acid-heptenyl and 3-decene base.
Term " alkoxyl group " is meant the alkyl that is connected with parent molecular moiety through Sauerstoffatom.The representational example of alkoxyl group is including, but not limited to methoxyl group, oxyethyl group, propoxy-, 2-propoxy-, butoxy, tert.-butoxy, pentyloxy, hexyloxy or the like.
Term " alkoxyl group alkoxyl group " is meant the alkoxyl group that is connected with parent molecular moiety through another alkoxyl group defined herein.The representational example of alkoxyl group alkoxyl group is including, but not limited to tert.-butoxy methoxyl group, 2-ethoxy ethoxy, 2-methoxy ethoxy and methoxymethoxy.
Term " alkoxyalkyl " is meant the alkoxyl group that is connected with parent molecular moiety through alkyl defined herein.The representational example of alkoxyalkyl is including, but not limited to tert.-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl and methoxymethyl.
Term " carbalkoxy " is meant the alkoxyl group that is connected with parent molecular moiety through carbonyl defined herein.The representational example of carbalkoxy is including, but not limited to methoxycarbonyl, ethoxycarbonyl and tertbutyloxycarbonyl.
Term " alkane (alkyl) oxygen base imines acid amides " is meant
Figure 405891DEST_PATH_IMAGE002
group.
Term " alcoxyl imido grpup " be meant through-C (=NH)-alkoxyl group that group (also it being defined as imino-) is connected with parent molecular moiety.The representational example of alcoxyl imido grpup is including, but not limited to imino-(methoxyl group) methyl, oxyethyl group (imino-) methyl and tert.-butoxy (imino-) methyl.
Term " alkoxyl group alkylsulfonyl " is meant the alkoxyl group that is connected with parent molecular moiety through alkylsulfonyl defined herein.The representational example of alkoxyl group alkylsulfonyl is including, but not limited to methoxyl group alkylsulfonyl, oxyethyl group alkylsulfonyl and propoxy-alkylsulfonyl.
Term " alkyl " is meant the straight or branched hydrocarbon that contains 1 to 6 carbon atom.The representational example of alkyl is including, but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec.-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl and n-hexyl.
In some cases, the carbon atom number in the hydrocarbyl substituent (for example, alkyl, thiazolinyl, alkynyl or naphthenic base) is through prefix " C x-C y-" expression, wherein x is the minimal number of the carbon atom in the substituting group, y is a maximum number.Thus, for example, " C 1-C 6-alkyl " be meant the alkyl substituent that contains 1 to 6 carbon atom.Further illustrate C 3-C 6-naphthenic base is meant the stable hydrocarbon basic ring that contains 3 to 6 carboatomic ring atoms.
Term " alkyl-NH-alkyl " is meant the alkyl that connects second alkyl defined herein through-NH-group.Said second alkyl is connected with parent molecular moiety.
Term " alkyl-carbonyl " is meant the alkyl that is connected with parent molecular moiety through carbonyl defined herein.The representational example of alkyl-carbonyl is including, but not limited to ethanoyl, 1-oxopropyl, 2,2-dimethyl--1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.
Term " alkyl-cycloalkyl " is meant the alkyl that is connected with parent molecular moiety through naphthenic base defined herein.The representational example of alkyl-cycloalkyl is including, but not limited to 4-ethyl cyclohexyl, 3-methylcyclopentyl and 2-sec.-propyl cyclopropyl.
Term " alkyl sulphonyl " is meant the alkyl that is connected with parent molecular moiety through alkylsulfonyl defined herein.The example of alkyl sulphonyl is including, but not limited to methyl sulphonyl and ethylsulfonyl.
Term " alkylthio " is meant the alkyl that is connected with parent molecular moiety through sulphur atom.The representational example of alkylthio is including, but not limited to methylthio group, ethylmercapto group, uncle's butylthio and own sulfenyl.
Term " amino " is-NR 90R 91, R wherein 90And R 91Be hydrogen independently of one another, alkyl, alkoxyl group, alkyl sulphonyl, aryl, aralkyl, aryloxy; Aryloxyalkyl group, aryl sulfonyl, alkyl-NH-alkyl, aryl-NH-alkyl, aralkyl, haloalkyl, aryl-heterocycle; Carboxyl, carboxyalkyl, carboxyl naphthenic base, naphthenic base, cycloalkyl oxy, naphthene sulfamide base; Heteroaryl, heteroaralkyl, heteroaryl oxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle; Heterocycle-NH-alkyl, heterocycle-alkyl, heterocycle-heterocycle, heterocycle oxyalkyl, heterocyclic oxy group, heterocycle alkylsulfonyl or hydroxyl.
Term " alkynyl " is meant the straight or branched hydrocarbyl group that contains 2 to 10 carbon atoms, preferred 2,3,4 or 5 carbon atoms, and contain at least one carbon-to-carbon triple bond.The representational example of alkynyl is including, but not limited to ethynyl, 1-proyl, 2-propynyl, 3-butynyl, valerylene base and ethyl acetylene base.
Term " amidine " or " imines acid amides " are meant
Figure 120382DEST_PATH_IMAGE003
group.
Term " carboxamido-group " is meant amino, alkylamino or the dialkyl amido that is connected with parent molecular moiety through carbonyl defined herein.The representational example of carboxamido-group is including, but not limited to aminocarboxyl, methylamino carbonyl, dimethylamino carbonyl and ethylmethylamino carbonyl.
Term " aryl " is meant phenyl, bicyclic aryl or three cyclophane bases.Bicyclic aryl be naphthyl, with naphthenic base, cycloalkenyl group, heteroaryl or heterocyclic fused phenyl defined herein.Bicyclic aryl must be connected with parent molecular moiety through the carbon atom arbitrary capable of using that is comprised in the benzyl ring.The representational example of bicyclic aryl is including, but not limited to dihydro indenyl, indenyl, naphthyl, dihydro naphthyl and tetralyl.Can through bicyclic aryl and with naphthenic base defined herein, phenyl, heteroaryl or the heterocyclic fused three ring condensed ring systems that illustrate.Three cyclophane bases are connected with parent molecular moiety through the either carbon atom that is comprised in the benzyl ring.The representational example of aryl is including, but not limited to anthryl; Phenanthryl,
Figure 515591DEST_PATH_IMAGE004
base, fluorenyl; Indanyl; Indenyl, naphthyl, phenyl and tetralyl.
Aryl of the present invention can be independently selected from following substituting group by 0,1,2,3,4 or 5 and replace: thiazolinyl, alkoxyl group, alkoxyl group alkoxyl group, alkoxyalkyl, carbalkoxy, alkoxycarbonyl alkyl, alkyl, alkyl-carbonyl; Alkyl sulphonyl, alkynyl, aryl, aralkoxy, aryl carbonyl, aryloxy, aryl sulfonyl, carboxyl; Carboxyalkyl, cyanic acid, cyanic acid alkyl, ethylidene dioxy base, formyl radical, halogenated alkoxy, haloalkyl, halogen; Heteroaryl, assorted aralkoxy, heteroaralkyl, heteroaryl carbonyl, heterocycle, heterocycle-alkoxyl group, heterocycle carbonyl; Heterocyclic oxy group, heterocycle alkylsulfonyl, hydroxyl, hydroxyalkyl, methylene radical dioxy base, nitro ,-C (O) N (H) S (O) 2Alkyl ,-R fR gN-, R fR gThe N alkyl, R fR gThe N carbonyl ,-N (H) C (O) N (H) (alkyl), and R fR gN alkylsulfonyl, wherein R fAnd R gBe independently selected from: hydrogen, alkyl, alkoxyalkyl, carbalkoxy, alkyl-carbonyl, alkyl sulphonyl, naphthenic base, haloalkyl, halogenated alkyl carbonyl and cycloalkylalkyl, wherein R fAnd R gThe naphthenic base of representative, the naphthenic base of cycloalkylalkyl are unsubstituted independently of one another, or are replaced by 1,2 or 3 substituting group that is independently selected from halogen, alkyl and haloalkyl.The heterocycle of the heterocycle of the heteroaryl of the aryl of the aryl of substituting group aryl, aralkoxy, the aryl of aryl carbonyl, aryloxy, the aryl of aryl sulfonyl, substituting group heteroaryl, heteroaralkyl, the heteroaryl of heteroaryl carbonyl, substituting group heterocycle, heterocycle carbonyl, the heterocycle of heterocyclic oxy group, heterocycle alkylsulfonyl can be chosen wantonly by 1,2 or 3 and be independently selected from following substituting group replacement: alkoxyl group, alkoxyalkyl, carbalkoxy; Alkyl, alkyl-carbonyl, alkynyl; Carboxyl, carboxyalkyl, cyanic acid; Haloalkyl, halogen, hydroxyl; Hydroxyalkyl, nitro, R fR gN-, R fR gThe N alkyl, R fR gN carbonyl and R fR gN alkylsulfonyl, wherein R fAnd R gSuch as this paper description.
Term " aralkoxy " is meant the aryl that is connected with parent molecular moiety through alkoxyl group defined herein.The representational example of aralkoxy is including, but not limited to the 2-phenyl ethoxy, 3-naphthalene-2-base propoxy-and 5-phenyl pentyloxy.
Term " aromatic alkoxy carbonyl " is meant the aralkoxy that is connected with parent molecular moiety through carbonyl defined herein.The representational example of aromatic alkoxy carbonyl is including, but not limited to carbobenzoxy-(Cbz) and naphthalene-2-base methoxycarbonyl.
Term " aralkyl " is meant the aryl that is connected with parent molecular moiety through alkyl defined herein.The representational example of aralkyl is including, but not limited to benzyl, 2-styroyl and 3-hydrocinnamyl.
Term " aryl carbonyl " is meant the aryl that is connected with parent molecular moiety through carbonyl defined herein.The example of aryl carbonyl is including, but not limited to benzoyl-and naphthoyl base.
Term " aryloxy " is meant the aryl that is connected with parent molecular moiety through Sauerstoffatom.Examples of aryloxy is including, but not limited to phenoxy and tolyloxy.
Term " aryloxyalkyl group " is meant the aryloxy that is connected with parent molecular moiety through alkyl defined herein.
Term " virtue (aryl) oxygen base imines acid amides " is meant
Figure 329963DEST_PATH_IMAGE005
group.
Term " aryl sulfonyl " is meant the aryl that is connected with parent molecular moiety through alkylsulfonyl defined herein.The representational example of aryl sulfonyl is including, but not limited to benzene sulfonyl, 4-bromobenzene sulphonyl and naphthyl alkylsulfonyl.
Term " carbonyl " is meant-C (O)-group.
Term " carboxyl " is meant-CO 2The H group.
Term " carboxyalkyl " is meant the carboxyl that is connected with parent molecular moiety through alkyl defined herein.The representational example of carboxyalkyl is including, but not limited to ethyloic, 2-propyloic and 3-carboxylic propyl group.
Term " carboxyl naphthenic base " is meant the carboxyl defined herein that is connected with parent molecular moiety through naphthenic base defined herein.
Term " combined therapy " is defined as: give the preparation of single pharmaceutical dosage, it comprises two or more therapeutical agents.
Term " cyanic acid " be meant through carbon be connected with parent molecular moiety-the CN group.
Term " cyanic acid alkyl " be meant through alkyl be connected with parent molecular moiety-the CN group.The representational example of " cyanic acid alkyl " is including, but not limited to 3-cyanic acid propyl group and 4-cyanic acid butyl.
Term " cyano amidine " is meant
Figure 90109DEST_PATH_IMAGE006
group.
Term " cycloalkyloxy " is meant the naphthenic base that is connected with parent molecular moiety through Sauerstoffatom.The example of cycloalkyloxy is including, but not limited to: cyclohexyl oxygen base and ring propoxy-.
Term " cycloalkyloxy alkyl " is meant the cycloalkyloxy that is connected with parent molecular moiety through alkyl, wherein alkyl such as defined herein.The representational example of cycloalkyloxy alkyl is including, but not limited to cyclobutoxy group methyl, cyclopentyloxy methyl, 2-(cyclopentyloxy) ethyl and cyclohexyl oxygen ylmethyl.
Term " naphthenic base " is meant monocycle, dicyclo or three-loop system.Single-loop system can be through comprising 3 to 4 carbon atom ((C 3-C 4) naphthenic base), 5 to 6 carbon atom ((C 5-C 6) naphthenic base), 3 to 6 carbon atom ((C 3-C 6) naphthenic base), 7 to 8 carbon atom ((C 7-C 8) naphthenic base) or 3 to 8 carbon atom ((C 3-C 8) naphthenic base) and the saturated cyclic hydrocarbons group illustrate.The example of single-loop system comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Bicyclic system can illustrate through the bridge joint single-loop system, and in this bridge joint single-loop system, monocyclic two non-adjacent carbonss connect through the alkylidene bridge of extra carbon atom between and three.The representational example of bicyclic system including, but not limited to: two the ring [3.1.1] heptyl, two the ring [2.2.1] heptyl, two the ring [2.2.2] octyl groups, two the ring [5.1.0] octyl groups, two the ring [3.2.2] nonyls, two the ring [3.3.1] nonyls and two the ring [4.2.1] nonyls.Bicyclic system can also be through illustrating with phenyl or heteroaryl ring condensed single-loop system.The representational example of bicyclic system including, but not limited to: 1,2,3, the 4-tetralyl, indanyl and 6,7-dihydro-5H-pentamethylene is [c] pyridyl also.Bicyclic cycloalkyl is connected with parent molecular moiety through being included in unsaturated naphthenic base intra-annular either carbon atom.Three-loop system can illustrate through bicyclic system, in this bicyclic system, two non-adjacent carbonss of dicyclo through a key or between one and three the alkylidene bridge of carbon atom connect.The representational example of three ring ring systems is including, but not limited to octahydro-2,5-methylene radical pentalene, three ring [3.3.1.0 3,7] nonyl and three ring [3.3.1.1 3,7] decyl (adamantyl).
Naphthenic base of the present invention can be independently selected from following substituting group by 0,1,2,3 or 4 and replace: alkyl, thiazolinyl, alkyl-NH-alkyl, alkyl-carbonyl, alkyl sulphonyl, alkylthio, aryl; Aralkyl, aryloxyalkyl group, aryl carbonyl, aryl sulfonyl, carboxyalkyl, carboxyl naphthenic base, cyanic acid; The cyanic acid alkyl, naphthenic base, naphthene base carbonyl, naphthene sulfamide base, halogen, haloalkyl, heterocycle carbonyl; The heterocycle alkylsulfonyl, heteroaryl, heteroaralkyl, heterocycle, heterocycle-alkyl, heterocycle oxyalkyl ,-NO 2,-NR 8-[C (R 9R 10)] p-C (O)-R 11,-[C (R 12R 13)] q-CR 12(OH)-R 14,-[C (R 12R 13)] q-C (O)-R 14,-CR 12=R 13-C (O)-R 14,-[C (R 12R 13)] q-S (O) 2-R 14,-[C (R 12R 13)] q-S (O)-R 14,-[C (R 12R 13)] q-S-R 14,-O-[C (R 12R 13)] q-C (O)-R 14,-OR 15,-N (R 16R 17), NR 8C (O) N (R 19R 20) ,-CO 2R 18,-C (O)-N (R 19R 20) ,-[C (R 12R 13)] p-C (O)-N (R 19R 20) ,-C (NH) NH 2,-C (R 21R 22)-OR 23, and-C (R 24R 25)-N (R 26R 27) ,-C (=NOH)-N (H) 2,-C (R 28R 29)-C (O) N (R 30R 31) ,-S (O) 2-N (R 32R 33) ,-S (O) 2-[C (R 9R 10)] p-C (O) N (R 32R 33), and-C (R 28R 29)-S (O) 2-N (R 32R 33), wherein
P is 1,2,3,4,5 or 6;
Q is 0,1,2,3,4,5 or 6;
R 8Be hydrogen, alkyl, carboxyalkyl, naphthenic base, carboxyl naphthenic base, aryl, aralkyl, aryloxyalkyl group, aryloxy, hydroxyl, alkoxyl group, cycloalkyl oxy, heterocyclic oxy group, heterocycle, heterocyclic radical alkyl or heterocycle oxyalkyl;
R 9And R 10Be hydrogen independently of one another, alkyl, carboxyl, carboxyalkyl, naphthenic base, carboxyl naphthenic base, aryl, aralkyl, aryloxyalkyl group, heterocycle, heterocyclic radical alkyl, or heterocycle oxyalkyl, or R 9And R 10The atom that is connected with them forms naphthenic base or heterocycle;
R 11Be hydrogen, alkyl, carboxyl, carboxyalkyl, naphthenic base, the carboxyl naphthenic base, aryl, aryloxy, aralkyl, aryloxyalkyl group, hydroxyl, alkoxyl group, cycloalkyl oxy, heterocyclic oxy group, heterocycle, the heterocyclic radical alkyl, the heterocycle oxyalkyl, or-N (R 28R 29);
R 12And R 13Be hydrogen independently of one another, alkyl, carboxyl, carboxyalkyl, naphthenic base, the carboxyl naphthenic base, aryl, aralkyl, aryloxyalkyl group, heterocycle, the heterocyclic radical alkyl, the heterocycle oxyalkyl or-N (R 28R 29), or R 12And R 13The atom that is connected with them forms naphthenic base or heterocycle;
R 14Be hydrogen, alkyl, carboxyl, carboxyalkyl, naphthenic base, the carboxyl naphthenic base, aryl, aralkyl, aryloxy, aryloxyalkyl group, hydroxyl, alkoxyl group, cycloalkyl oxy, heterocyclic oxy group, heterocycle, the heterocyclic radical alkyl, the heterocycle oxyalkyl, or-N (R 30R 31);
R 15Be hydrogen, alkyl, alkyl-carbonyl, carboxyalkyl, naphthenic base, carboxyl naphthenic base, aryl, aralkyl, aryloxyalkyl group, haloalkyl, heterocycle, heterocyclic radical alkyl or heterocycle oxyalkyl;
R 16And R 17Be hydrogen independently of one another, alkyl, alkyl-carbonyl, carboxyalkyl, naphthenic base, carboxyl naphthenic base; Aryl, aralkyl, aryloxyalkyl group, haloalkyl, heterocycle, heterocyclic radical alkyl; The heterocycle oxyalkyl, alkyl sulphonyl, naphthene sulfamide base, aryl sulfonyl, formyl radical or heterocycle alkylsulfonyl, or R 16And R 17The atom that is connected with them forms heterocycle;
R 18Be hydrogen, alkyl, carboxyalkyl, naphthenic base, carboxyl naphthenic base, aryl, aralkyl, aryloxyalkyl group, heterocycle, heterocyclic radical alkyl or heterocycle oxyalkyl;
R 19And R 20Be hydrogen independently of one another, alkyl, carboxyl, carboxyalkyl, naphthenic base, cycloalkyl oxy; The carboxyl naphthenic base, aryl, aralkyl, aryloxy, aryloxyalkyl group, heteroaralkyl; Heterocycle, heterocyclic radical alkyl, heterocycle oxyalkyl, heterocyclic oxy group, hydroxyl, alkoxyl group; Alkyl sulphonyl, the naphthene sulfamide base, aryl sulfonyl, the heterocycle alkylsulfonyl, or-[C (R 12R 13)] qC (O) R 14, or R 19And R 20The atom that is connected with them forms heterocycle;
R 21, R 22And R 23Be hydrogen independently of one another, alkyl, carboxyalkyl, carboxyl naphthenic base, naphthenic base, haloalkyl, aryl, heterocycle or heterocyclic radical alkyl;
R 24And R 25Be hydrogen independently of one another, alkyl, alkyl-carbonyl, alkyl sulphonyl, carboxyalkyl, carboxyl naphthenic base, naphthene base carbonyl, naphthene sulfamide base, aryl carbonyl, aryl sulfonyl, heterocycle carbonyl, heterocycle alkylsulfonyl, naphthenic base, aryl or heterocycle;
R 26And R 27Be hydrogen independently of one another, alkyl, alkyl-carbonyl, alkyl sulphonyl, carboxyalkyl; The carboxyl naphthenic base, naphthene base carbonyl, naphthene sulfamide base, aryl carbonyl, aryl sulfonyl; The heterocycle carbonyl, heterocycle alkylsulfonyl, hydroxyl, alkoxyl group, cycloalkyl oxy; Aryloxy, heterocyclic oxy group, naphthenic base, aryl or heterocycle, or R 26And R 27The atom that is connected with them forms heterocycle;
R 28And R 29Be hydrogen or alkyl independently of one another when occurring at every turn;
R 30And R 31Be hydrogen independently of one another when occurring at every turn, alkyl, alkyl-carbonyl, alkoxyl group, alkyl sulphonyl, aryl; Aryl carbonyl, aryloxy, aryl sulfonyl, carboxyalkyl, carboxyl naphthenic base, naphthenic base; Naphthene base carbonyl, cycloalkyl oxy, naphthene sulfamide base, heteroaryl, heteroaryl carbonyl, heteroaryloxy; Heteroarylsulfonyl, heterocycle, heterocycle carbonyl, heterocyclic oxy group, heterocycle alkylsulfonyl or hydroxyl, or R 30And R 31The atom that is connected with them forms heteroaryl or heterocycle; With
R 32And R 33When occurring, be selected from hydrogen, alkyl, alkoxyl group, alkyl sulphonyl, aryl, aralkyl, aryloxy independently of one another at every turn; Aryloxyalkyl group, aryl sulfonyl, alkyl-NH-alkyl, aryl-NH-alkyl, aralkyl, haloalkyl, aryl-heterocycle; Carboxyl, carboxyalkyl, carboxyl naphthenic base, naphthenic base, cycloalkyl oxy, naphthene sulfamide base, heteroaryl; Heteroaralkyl, heteroaryl oxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocycle-NH-alkyl; The heterocyclic radical alkyl, heterocycle-heterocycle, heterocycle oxyalkyl, heterocyclic oxy group, heterocycle alkylsulfonyl and hydroxyl, or R 32And R 33The atom that is connected with them forms heterocycle.
Term " cycloalkylalkyl " is meant the naphthenic base that is connected with parent molecular moiety through alkyl defined herein.The representational example of cycloalkylalkyl is including, but not limited to cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl and suberyl methyl.
Term " naphthene base carbonyl " is meant the naphthenic base that is connected with parent molecular moiety through carbonyl defined herein.The representational example of naphthene base carbonyl is including, but not limited to cyclopropyl carbonyl, 2-cyclobutyl carbonyl and cyclohexyl-carbonyl.
Term " naphthene sulfamide base " is meant the naphthenic base that is connected with parent molecular moiety through alkylsulfonyl defined herein.The representational example of naphthene sulfamide base is including, but not limited to cyclohexyl alkylsulfonyl and cyclobutyl alkylsulfonyl.
Term " formyl radical " is meant-C (O) H group.
Term " halogen " or " halo " are meant-Cl ,-Br ,-I or-F.
Term " halogenated alkoxy " is meant at least one halogen that is connected with parent molecular moiety through alkoxyl group defined herein.The representational example of halogenated alkoxy is including, but not limited to Fluoroalkyloxy, chlorine alkoxyl group, bromine alkoxyl group and iodo alkoxyl group, for example fluorine methoxyl group; Difluoro-methoxy, trifluoromethoxy, 2-fluorine oxyethyl group, trifluoromethoxy; 2,2,2-trifluoro ethoxy and five fluorine oxyethyl groups.
Term " haloalkyl " is meant at least one halogen that is connected with parent molecular moiety through alkyl defined herein.The representational example of haloalkyl is including, but not limited to difluoromethyl, chloromethyl, 2-fluoro ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl group and 2-chloro-3-fluorine amyl group.
Term " halogenated cycloalkyl " is meant at least one halogen that is connected with parent molecular moiety through naphthenic base defined herein.The representational example of halogenated cycloalkyl is including, but not limited to the fluorine cyclohexyl, bromine cyclopropyl and trans-2,3-dichloro cyclopentyl.
Term " halogenated cycloalkyl alkyl " is meant the halogenated cycloalkyl defined herein that is connected with parent molecular moiety through alkyl.The representational example of halogenated cycloalkyl alkyl is including, but not limited to (4-fluorine cyclohexyl) methyl, (2,2-difluoro cyclobutyl) methyl or the like.
Term " halogenosulfanes oxygen base " is meant at least one halogen that is connected with parent molecular moiety through thioalkoxy group defined herein.The representational example of halogenosulfanes oxygen base is including, but not limited to 2-chloroethyl sulfane and trifluoromethyl sulfane.
Term " heteroaryl " is meant bicyclic heteroaryl or bicyclic heteroaryl.Bicyclic heteroaryl is to comprise at least one heteroatomic 5 or 6 yuan of ring, and wherein heteroatoms is selected from nitrogen, oxygen and sulphur.5 yuan of rings comprise two two keys, and 6 yuan of rings comprise three two keys.5 or 6 yuan of heteroaryls are connected with parent molecular moiety through either carbon atom or the arbitrary commutable nitrogen-atoms that is included within the heteroaryl, and condition is: keep correct valency.The representational example of bicyclic heteroaryl is including, but not limited to furyl, imidazolyl, different
Figure 357142DEST_PATH_IMAGE007
azoles base; Isothiazolyl;
Figure 556042DEST_PATH_IMAGE007
di azoly,
Figure 162604DEST_PATH_IMAGE007
azoles base, pyridyl; Pyridazinyl; Pyrimidyl, pyrazinyl, pyrazolyl; Pyrryl; Tetrazyl, thiadiazolyl group, thiazolyl; Thienyl, triazolyl and triazinyl.Bicyclic heteroaryl comprises: with phenyl condensed bicyclic heteroaryl, or with Cycloalkylfused bicyclic heteroaryl, or with cycloalkenyl group condensed bicyclic heteroaryl, or with bicyclic heteroaryl condensed bicyclic heteroaryl.Bicyclic heteroaryl is connected with parent molecular moiety through either carbon atom or the arbitrary commutable nitrogen-atoms that is included within the bicyclic heteroaryl, and condition is: keep correct valency.The representational example of bicyclic heteroaryl is including, but not limited to azaindolyl, benzimidazolyl-, benzofuryl; Benzo
Figure 155968DEST_PATH_IMAGE007
di azoly, benzisoxa
Figure 910297DEST_PATH_IMAGE007
azoles, benzisothiazole; Benzo
Figure 584992DEST_PATH_IMAGE007
azoles, 1, the 3-benzothiazolyl; Benzothienyl; Scold Lin Ji, furo pyridine, indyl; Indazolyl; Isobenzofuran-base, isoindolyl, isoquinolyl; Naphthyridinyl;
Figure 108377DEST_PATH_IMAGE007
azoles and pyridine, 1H-pyrrolo-[2,3-b] pyridyl; Quinolyl, quinoxalinyl and thienopyridine base.
Heteroaryl can be chosen wantonly by 1,2,3 or 4 and be independently selected from following substituting group replacement: acyloxy, thiazolinyl, alkoxyl group, carbalkoxy, alkyl, alkyl-carbonyl, alkyl sulphonyl; Alkylthio, alkynyl, carboxamido-group, aryl, aryloxy, carboxyl, carboxyalkyl; Cyanic acid, cyanic acid alkyl, naphthenic base, cycloalkyloxy, formyl radical, halogenated alkoxy, haloalkyl; Halogen, halogenosulfanes oxygen base, heteroaryl, thioalkoxy group, sulfenyl cycloalkyloxy, sulphur aryloxy, nitro and-NR 96R 97, R wherein 96And R 97Be hydrogen independently, alkoxyalkyl, carbalkoxy, alkyl, alkyl-carbonyl, alkyl sulphonyl, aryl, naphthenic base, haloalkyl, heteroaryl, or heterocycle, or R 96And R 97The nitrogen that is connected with them forms heterocycle.In addition, nitrogen heteroatom can be chosen wantonly by quaternized or be oxidized to corresponding N-oxide compound.
The term that this paper uses " assorted aralkoxy " is meant the heteroaryl that is connected with parent molecular moiety through alkoxyl group defined herein.The representational example of assorted aralkoxy is including, but not limited to furans-3-ylmethoxy, 1H-imidazoles-2-ylmethoxy, 1H-imidazol-4 yl methoxyl group, 1-(pyridin-4-yl) oxyethyl group; The pyridin-3-yl methoxyl group, 6-chloro-pyridine-3-ylmethoxy, pyridin-4-yl methoxyl group, (6-(trifluoromethyl) pyridin-3-yl) methoxyl group; (6-(cyanic acid) pyridin-3-yl) methoxyl group, (2-(cyanic acid) pyridin-4-yl) methoxyl group, (5-(cyanic acid) pyridine-2-yl) methoxyl group; (2-(chlorine) pyridin-4-yl) methoxyl group, pyrimidine-5-ylmethoxy, 2-(pyrimidine-2-base) propoxy-; 1,3-thiazoles-4-ylmethoxy, thiophene-2-ylmethoxy and thiene-3-yl-methoxyl group.
Term " heteroaralkyl " is meant the heteroaryl that is connected with parent molecular moiety through alkyl defined herein.
Term " heteroaryl carbonyl " is meant the heteroaryl that is connected with parent molecular moiety through carbonyl defined herein.The representational example of heteroaryl carbonyl is including, but not limited to: furans-3-base carbonyl, 1H-imidazoles-2-base carbonyl, 1H-imidazol-4 yl carbonyl; The pyridin-3-yl carbonyl, 6-chloro-pyridine-3-base carbonyl, pyridin-4-yl carbonyl; (6-(trifluoromethyl) pyridin-3-yl) carbonyl, (6-(cyanic acid) pyridin-3-yl) carbonyl, (2-(cyanic acid) pyridin-4-yl) carbonyl; (5-(cyanic acid) pyridine-2-yl) carbonyl, (2-(chlorine) pyridin-4-yl) carbonyl, pyrimidine-5-base carbonyl; The pyrimidine-2-base carbonyl, thiophene-2-base carbonyl and thiene-3-yl-carbonyl.
Term " heterocycle " or " heterocyclic " are meant monocyclic heterocycles, bicyclic heterocycle or tricyclic heterocyclic.Monocyclic heterocycles is to comprise at least one heteroatomic 3,4,5,6 or 7 yuan of ring, and wherein heteroatoms is independently selected from O, N and S.3-or 4-unit ring comprise 1 heteroatoms that is selected from O, N and S.5-unit ring comprises zero or two keys and one, two or three heteroatomss that are selected from O, N and S.6-or 7-unit ring comprise zero, one or two pair key and one, two, three or four heteroatomss that are selected from O, N and S, and condition is: when this ring combined with substituting group, it can not form aromatic ring with the substituting group change.Monocyclic heterocycles is connected with parent molecular moiety through either carbon atom or the arbitrary nitrogen-atoms that is included within the monocyclic heterocycles.
The representational example of monocyclic heterocycles is including, but not limited to azetidinyl, azepan base, '-aziridino; The Diazesuberane base, 1,3-two
Figure 538222DEST_PATH_IMAGE007
alkyl; 1,3-dioxolanyl, 1; 3-dithia cyclopentyl, 1,3-dithian base; Imidazolinyl, imidazolidyl, isothiazoline base; The isothiazole alkyl, different
Figure 717530DEST_PATH_IMAGE007
azoles quinoline base, different
Figure 992654DEST_PATH_IMAGE007
oxazolidinyl; Morpholinyl,
Figure 636125DEST_PATH_IMAGE007
bisoxazoline base,
Figure 971291DEST_PATH_IMAGE007
two oxazolidinyls;
Figure 637896DEST_PATH_IMAGE007
azoles quinoline base,
Figure 716710DEST_PATH_IMAGE007
oxazolidinyl, piperazinyl; Piperidyl, pyranyl, pyrazolinyl; Pyrazolidyl; Pyrrolinyl, pyrrolidyl, tetrahydrofuran base; THP trtrahydropyranyl; Tetrahydro-thienyl, Thiadiazoline base, thiadiazoles alkyl; Thiazolinyl; Thiazolidyl, parathiazan base, 1; 1-dioxo parathiazan base (parathiazan sulfone), sulphur pyranyl and trithian base (trithianyl).Bicyclic heterocycle is: with phenyl condensed monocyclic heterocycles, with Cycloalkylfused monocyclic heterocycles, with cycloalkenyl group condensed monocyclic heterocycles, or with monocyclic heterocycles condensed monocyclic heterocycles.Bicyclic heterocycle is connected with parent molecular moiety through either carbon atom or the arbitrary nitrogen-atoms that is included within the monocyclic heterocycles.The representational example of bicyclic heterocycle is including, but not limited to: azabicyclo [3.2.0] heptan-3-base, 1-azabicyclo [2.2.2] octyl group (quinuclidinyl), 1,3-benzodioxole base, 1; 3-benzo dithia cyclopentenyl, 2,3-dihydro-1,4-benzo dioxin base, 3; 7-diazabicyclo [3.3.1] nonyl, 3,9-diazabicyclo [4.2.1] nonyl, 2,3-dihydro-1-benzofuryl; 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indyl, hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-Ji, indolinyl, isoindolinyl, 2,3; 4,5-tetrahydrochysene-1H-3-benzo-aza base, octahydro pyrrolo-[3,4-c] pyrryl, tetrahydro-1 H-pyrrolo also [3; 4-b] and pyridine-6 (2H, 7H, 7aH)-and Ji, 3-azabicyclo [3.2.0] heptane; Rubane and 1,2,3, the 4-tetrahydric quinoline group.The representational example of tricyclic heterocyclic system is including, but not limited to azepine-adamantyl; Oxa--adamantyl and 7; 8,9,10-tetrahydrochysene-6H-[1; 3] dioxole [4,5-g] [3] benzo-aza
Figure 924018DEST_PATH_IMAGE008
base also.
Heterocycle can be independently selected from following substituting group by 0,1,2,3,4,5,6,7,8 or 9 and replace: acyl group, acyloxy, thiazolinyl, alkoxyl group, alkoxyl group alkoxyl group, alkoxyalkyl, carbalkoxy, alcoxyl imido grpup; The alkoxyl group alkylsulfonyl, alkyl, alkyl-carbonyl, alkyl sulphonyl, alkylthio, alkynyl, carboxamido-group, aryl; Aryl alkyl carbonyl oxygen, aralkyl, aryloxy, aryloxyalkyl group, carboxyl, cyanic acid, cyanic acid alkyl, naphthenic base; Formyl radical, halogenated alkoxy, haloalkyl, halogen, heteroaryl, heteroaralkyl, heteroaryl carbonyl; The heteroaryl oxyalkyl, hydroxyl, hydroxyalkyl, sulfydryl, nitro, oxo ,-alkyl NR 98R 99,-NR 98R 99, (NR 98R 99) carbonyl ,-SO 2N (R 98) (R 99) ,-SO 2R 98,-NR 98(C=O) NR 98R 99,-NR 98(C=O) O alkyl and-N (R 98) SO 2(R 99), R wherein 98And R 99Be selected from acyl group independently of one another, alkoxyalkyl, carbalkoxy, alkyl, alkyl-carbonyl; Alkyl-cycloalkyl, alkyl sulphonyl, carboxamido-group, aryl, cyanic acid alkyl; The cycloalkyloxy alkyl, naphthenic base, haloalkyl, halogenated cycloalkyl, halogenated cycloalkyl alkyl; Heteroaryl, heterocycle, hydrogen, formyl radical, hydroxyl and hydroxyalkyl.In addition, nitrogen heteroatom can be chosen wantonly by quaternized or be oxidized to corresponding N-oxide compound.
The term " heterocyclic radical alkoxyl group " that this paper uses is meant the heterocyclic radical that is connected with parent molecular moiety through alkoxyl group defined herein.The representational example of heterocyclic radical alkoxyl group is including, but not limited to 2-morpholine-4-base oxethyl, 2-morpholine-4-base oxethyl and (THF-2-yl) methoxyl group.
Term " heterocyclic radical alkyl " is meant the heterocycle that is connected with parent molecular moiety through alkyl defined herein.The representational example of heterocyclic radical alkyl is including, but not limited to (tetramethyleneimine-2-yl) methyl, 2-(morpholine-4-yl) ethyl and (THF-3-yl) methyl.
Term " heterocycle carbonyl " is meant the heterocycle that is connected with parent molecular moiety through carbonyl defined herein.The representational example of heterocycle carbonyl is including, but not limited to the piperidino carbonyl, 4-morpholinyl carbonyl, pyridin-3-yl carbonyl and quinoline-3-base carbonyl.
Term " heterocycle-heterocycle " is meant through second heterocycle that heterocycle is connected with parent molecular moiety defined herein.
Term " heterocycle oxyalkyl " is meant the heterocyclic oxy group that is connected with parent molecular moiety through alkyl defined herein.
Term " heterocycle alkylsulfonyl " is meant the heterocycle that is connected with parent molecular moiety through alkylsulfonyl defined herein.The representational example of heterocycle alkylsulfonyl is including, but not limited to the piperidino alkylsulfonyl, 4-morpholinyl alkylsulfonyl, pyridin-3-yl alkylsulfonyl and quinoline-3-base alkylsulfonyl.
Term " hydroxyl " is meant-the OH group.
Term " hydroxyalkyl " is meant at least one hydroxyl that is connected with parent molecular moiety through alkyl defined herein.The representational example of hydroxyalkyl is including, but not limited to methylol, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyl amyl group and 2-ethyl-4-hydroxyl heptyl.
Term " hydroxyl imide acid amides " is meant group.
Term " imino-" is meant-C (=NH)-group.
Term " sulfydryl " is meant-the SH group.
Term " nitro " is meant-NO 2Group.
Term " oxo " be meant (=O).
Term " parenteral " is meant mode of administration, comprises that intravenously, intramuscular, intraperitoneal, breastbone are interior, subcutaneous, intra-articular injection and injection.
Term " pharmacologically acceptable salt " or " salt " are meant: in reliable medical judgment scope; Be fit to contact with zootic tissue and use and do not have those salt of excessive toxicity, pungency, allergic effect reaction or the like, and match with the validity of rational benefit/dangerous ratio and the use of its target with the people.Pharmacologically acceptable salt is well known in the art.Salt can be during the final separation of The compounds of this invention and purifying in-situ preparing, or react with appropriate organic through free alkali functional group and to separate preparation.Representational acid salt is including, but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate; Hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate; Enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (isethionate); Lactic acid salt, PHENRAMINE MALEATE, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, embonate; YM 115H salt, persulphate, 3-phenpropionate, picrate, pivalate, propionic salt, SUMATRIPTAN SUCCINATE; Tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.In addition, can use for example rudimentary halon reagent (the for example chlorine of methyl, ethyl, propyl group and butyl, bromine and iodide); Sulfuric acid dialkyl (for example sulfuric acid dimethyl-, diethylammonium, dibutyl and diamyl ester); Long-chain halogenide (the for example chlorine of decyl, lauryl, tetradecyl and stearyl, bromine and iodide); It is quaternized that aralkyl halide (for example, benzyl and phenethyl bromide) and other reagent will comprise the group of basic nitrogen.Obtain water or the soluble or dispersible products of oil thus.
The example that can be used to form the acid of pharmaceutically acceptable acid additive salt comprises: mineral acid, for example, and hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid, for example, oxalic acid, toxilic acid, succsinic acid and Citric Acid.Base addition salt can final separate and the purifying The compounds of this invention during in-situ preparing; Part through comprising carboxylic acid and suitable alkali (for example, the oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate) or react with ammonia or organic primary, second month in a season or tertiary amine prepares.Pharmacologically acceptable salt including, but not limited to: based on basic metal or earth alkali metal, for example the positively charged ion of lithium, sodium, potassium, calcium, magnesium and aluminium salt and nontoxic season ammonia and amine positively charged ion; Comprise ammonium, tetramethylammonium, Tetrylammonium; Ammonium methyl, Dimethyl Ammonium, trimethyl ammonium; Triethyl ammonium, diethyl ammonium, ethyl ammonium or the like.Other the representational organic amine that can be used for forming base addition salt comprises: the ethylene ammonium; The ethanol ammonium; Di-alcohol ammonium, piperidines
Figure 757162DEST_PATH_IMAGE010
and piperazine
Figure 47329DEST_PATH_IMAGE010
.
Term " pharmaceutically acceptable ester " or " ester " are meant the ester of the The compounds of this invention of hydrolysis in vivo, and comprise those esters that easily in human body, decompose generation parent compound or its salt.The example of pharmaceutically useful non-toxic ester of the present invention is including, but not limited to C 1-C 6Alkyl ester and C 5-C 7Cycloalkyl ester.The ester of formula (I) compound can prepare according to ordinary method.React with acid and alkyl carboxylic acid (for example acetate) or react through the compound that comprises hydroxyl, can pharmaceutically acceptable ester be connected on the hydroxyl with acid and aryl carboxylic acid (for example phenylformic acid).Comprise at compound under the situation of carboxyl, the reaction that pharmaceutically acceptable ester can be through this compound and alkali (for example triethylamine) and alkylogen (for example methyl-iodide, benzyl iodide, cyclopentyl iodine or trifluoromethanesulfonic acid alkyl ester), prepare by the compound that comprises carboxyl.They can also prepare through the reaction of compound with acid (for example hydrochloric acid) and alcohol (for example ethanol or methyl alcohol).
Term " pharmaceutically acceptable acid amides " or " acid amides " are meant derived from following of the present invention nontoxic acid amides: ammonia, uncle C 1-C 3Alkylamine, uncle C 4-C 6Alkylamine, secondary C 1-C 2Dialkylamine and secondary C 3-C 6Dialkylamine.Under the situation of secondary amine, amine can also be 5-or the 6-unit heterocycle form that comprises a nitrogen-atoms.The acid amides of formula (I) compound can prepare according to ordinary method.Pharmaceutically acceptable acid amides can be through comprising amino compound and alkyl acid anhydrides, aryl acid anhydrides, acyl halide or the reaction of aroyl halogen, being prepared by the compound that comprises uncle or secondary amine group.Comprise at compound under the situation of carboxyl, the reaction that pharmaceutically acceptable acid amides can be through this compound and alkali (for example triethylamine), dewatering agent (for example NSC 57182 or carbonyl dimidazoles) and alkylamine, dialkylamine (for example methylamine, diethylamine and piperidines), prepare by the compound that comprises carboxyl.They can also be in dehydration conditions (for example, add molecular sieve) reaction through compound and acid (for example sulfuric acid) and alkyl carboxylic acid (for example acetate) or prepare down with the reaction of sour and aryl carboxylic acid (for example phenylformic acid).Compsn can comprise the The compounds of this invention of pharmaceutically acceptable prodrug form.
Term " pharmaceutically acceptable prodrug " or " prodrug " are meant the prodrug of The compounds of this invention; It is in reliable medical judgment scope; Be fit to contact use with zootic tissue and do not have excessive toxicity, pungency, allergic effect reaction or the like, and match with the validity of rational benefit/dangerous ratio with its target use with the people.Prodrug of the present invention can be converted into the parent compound of formula (I) apace in vivo, for example, and through hydrolysis.Detailed commentary be provided in following in: people such as Higuchi; Pro-drugs as Novel Delivery Systems; V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed.; Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
Term " pharmaceutically acceptable carrier " or " carrier " are meant the formulation auxiliary agents of nontoxic inert solid, semisolid or liquid filler, thinner, sealing substance or any kind.Some examples that can serve as the material of pharmaceutically acceptable carrier are: sugar, lactose for example, dextrose plus saccharose; Starch, for example W-Gum and yam starch; Mierocrystalline cellulose and its verivate, Xylo-Mucine for example, TKK 021 and FM; The powder tragacanth; Fructus Hordei Germinatus; Gel; Talcum powder; Theobroma oil and suppository paraffin; Oil, peanut oil for example, oleum gossypii seminis, Thistle oil, til, sweet oil, Semen Maydis oil and VT 18; Glycol, for example Ucar 35; Ester, for example OE and Laurate ethyl; Agar; Buffer reagent, for example Marinco H and white lake; Lalgine; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol; And phosphate buffer soln; And other nontoxic consistency lubricant, for example Sodium Lauryl Sulphate BP/USP and Magnesium Stearate, and tinting material; Release agent, coating agent, sweeting agent; Seasonings and perfume compound, according to formulation art technician's judgement, sanitas and inhibitor can also be present in the compsn.
Term " alkylsulfonyl " is meant-SO 2-group.
Phrase " treatment significant quantity " is meant at the sufficient amount that is applicable to sanatory compound under the rational benefit of any treatment/dangerous ratio condition.
Solid, semisolid or the liquid filler that general reference pharmacy that term " is treated suitable vehicle " is suitable, thinner, sealing substance, formulation auxiliary agents or the like.
The pharmaceutically active compound that bio-transformation forms in the body of term " is treated suitable meta-bolites " general reference through type I compound.
Term " thioalkoxy group " is meant the alkyl that is connected with parent molecular moiety through sulphur atom.The representational example of thioalkoxy group is including, but not limited to methylthio group, ethylmercapto group, uncle's butylthio and own sulfenyl.
Term " thioamides " is meant
Figure 989877DEST_PATH_IMAGE011
group.
Term " sulfo-cycloalkyloxy " is meant the naphthenic base that is connected with parent molecular moiety through sulphur atom.The example of sulfo-cycloalkyloxy is including, but not limited to cyclopentyl sulfane and cyclohexyl sulfane.
Term " thio-aryloxy " is meant the aryl that is connected with parent molecular moiety through sulphur atom.The example of thio-aryloxy is including, but not limited to thiophene oxy and tolyl sulfane.
Compound of the present invention
An embodiment relates to the compound of formula (I)
Figure 427811DEST_PATH_IMAGE001
(I),
Wherein
L is-(CH 2) n-,-(CR 38R 39) m-X-(CR 38R 39) n-or-(CR 38R 39) m-X-(CR 38R 39) n-Y-;
M is 0,1 or 2 when occurring at every turn independently;
N is 0,1 or 2 when occurring at every turn independently;
R 1Be naphthenic base or heterocycle;
R 2Be hydrogen, alkyl or aryl; Or R 1And R 2The atom that is connected with them forms heterocycle; Or R 2And R 3The atom that is connected with them forms heterocycle;
R 3And R 4Be hydrogen independently, alkyl or cycloalkyl; Or R 3And R 4The atom that is connected with them forms naphthenic base, heterocycle, heteroaryl or aryl;
R 5Be hydrogen, alkyl, amino, aryl, naphthenic base, heteroaryl or heterocycle, condition is: when L is-(CR 38R 39) m-X-(CR 38R 39) nDuring-Y-, R 5Not amino; Or R 4And R 5The atom that is connected with them forms naphthenic base or heterocycle;
X is-O-,-S-, and-S (O)-,-S (O) 2-,-NR 36-or-CR 36R 37-;
Y is O or NR 40
R 36And R 37Be hydrogen or alkyl independently when occurring at every turn; Or R 36And R 2The atom that is connected with them forms heterocycle;
R 38, R 39And R 40Be hydrogen or alkyl independently when occurring at every turn;
W is N-CN, N-OR 6, N-R 6Or S; With
R 6Be hydrogen, alkyl or aryl; Or
Its pharmacologically acceptable salt, ester, acid amides, N-oxide compound or prodrug.
Another embodiment is the compound of formula (I), wherein R 1It is naphthenic base.
Another embodiment is the compound of formula (I), wherein R 1It is heterocycle.
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following naphthenic base or heterocycle:
Figure 848428DEST_PATH_IMAGE012
Figure 273330DEST_PATH_IMAGE013
。
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following naphthenic base or heterocycle:
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following naphthenic base or heterocycle:
Figure 312010DEST_PATH_IMAGE015
。
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following naphthenic base:
Figure 474001DEST_PATH_IMAGE016
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following naphthenic base:
Figure 535498DEST_PATH_IMAGE017
。
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following naphthenic base:
Wherein A is a defined substituting group in " naphthenic base " in the definitional part of term.
Another embodiment is the compound of formula (I), wherein R 1Be following naphthenic base:
Figure 170059DEST_PATH_IMAGE019
。
Another embodiment is the compound of formula (I), wherein R 1Be the naphthenic base of formula (iia):
Figure 198057DEST_PATH_IMAGE020
,
Wherein A is a defined substituting group in " naphthenic base " in the definitional part of term.
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following heterocycle:
Figure 379640DEST_PATH_IMAGE021
。
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following heterocycle:
Figure 506996DEST_PATH_IMAGE022
。
Another embodiment is the compound of formula (I), wherein R 1Be to be selected from following heterocycle:
Figure 406819DEST_PATH_IMAGE023
or
Corresponding N-oxide compound (xvi) and (xvii)
Figure 972929DEST_PATH_IMAGE024
。
Another embodiment is the compound of formula (I), wherein R 1Be heterocycle, it is an azaadamantane.
Another embodiment is the compound of formula (I), wherein R 1Be selected from the substituted naphthenic base of following substituting group by 0,1,2,3 or 4: alkyl, thiazolinyl, alkyl-NH-alkyl, alkyl-carbonyl, alkyl sulphonyl, alkylthio, aryl; Aralkyl, aryloxyalkyl group, aryl carbonyl, aryl sulfonyl, carboxyalkyl, carboxyl naphthenic base, cyanic acid; The cyanic acid alkyl, naphthenic base, naphthene base carbonyl, naphthene sulfamide base, halogen, haloalkyl, heterocycle carbonyl; The heterocycle alkylsulfonyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclic radical alkyl, heterocycle oxyalkyl ,-NO 2,-NR 8-[C (R 9R 10)] p-C (O)-R 11,-[C (R 12R 13)] q-CR 12(OH)-R 14,-[C (R 12R 13)] q-C (O)-R 14,-CR 12=R 13-C (O)-R 14,-[C (R 12R 13)] q-S (O) 2-R 14,-[C (R 12R 13)] q-S (O)-R 14,-[C (R 12R 13)] q-S-R 14,-O-[C (R 12R 13)] q-C (O)-R 14,-OR 15,-N (R 16R 17), NR 8C (O) N (R 19R 20) ,-CO 2R 18,-C (O)-N (R 19R 20) ,-[C (R 12R 13)] p-C (O)-N (R 19R 20) ,-C (NH) NH 2,-C (R 21R 22)-OR 23And-C (R 24R 25)-N (R 26R 27) ,-C (=NOH)-N (H) 2,-C (R 28R 29)-C (O) N (R 30R 31) ,-S (O) 2-N (R 32R 33) ,-S (O) 2-[C (R 9R 10)] p-C (O) N (R 32R 33) and-C (R 28R 29)-S (O) 2-N (R 32R 33); Wherein p, q, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 25, R 26, R 27, R 28, R 29, R 30, R 31, R 32And R 33Definition like " naphthenic base " in the definition of term is said.
Another embodiment is the compound of formula (I), wherein R 1Being selected from following substituting group by 0,1,2,3 or 4 replaces: alkyl sulphonyl, cyanic acid, halogen ,-C (R 12R 13)-C (O)-R 14,-OR 15,-CO 2R 18,-C (O)-N (R 19R 20) and-S (O) 2-N (R 32R 33).
Another embodiment is the compound of formula (I), wherein R 1Being selected from following substituting group by 0,1 or 2 replaces: fluorine, methyl sulphonyl, cyanic acid ,-OH ,-OCH 3,-OCF 3,-OCHF 2,-CO 2H ,-CH 2-CO 2H ,-CH (CH 3)-CO 2H ,-C (CH 3) 2-CO 2H ,-CHF 2,-CH (CH 3) (OH) ,-C (CH 3) 2(OH) ,-CH 2OH ,-C (O)-NH 2With-S (O) 2-NH 2
Another embodiment is the compound of formula (I), wherein R 1Being selected from following substituting group by at least one replaces: fluorine, methyl sulphonyl, cyanic acid ,-OH ,-CO 2H ,-CH 2-CO 2H ,-CH (CH 3)-CO 2H ,-C (CH 3) 2-CO 2H ,-CH (CH 3) (OH) ,-C (O)-NH 2With-S (O) 2-NH 2
Another embodiment is the compound of formula (I), wherein R 1Being selected from following substituting group by 0,1,2,3 or 4 replaces: alkyl sulphonyl, cyanic acid ,-OR 15,-CO 2R 18,-C (O)-N (R 19R 20) and-S (O) 2-N (R 32R 33).
Another embodiment is the compound of formula (I), wherein R 2Be hydrogen, alkyl or aryl.
Another embodiment is the compound of formula (I), wherein R 2Be hydrogen.
Another embodiment is the compound of formula (I), wherein R 2It is alkyl.
Another embodiment is the compound of formula (I), wherein R 2It is aryl.
Another embodiment is the compound of formula (I), wherein R 1And R 2The atom that is connected with them forms heterocycle.
Another embodiment is the compound of formula (I), wherein R 3And R 4Each is hydrogen naturally.
Another embodiment is the compound of formula (I), wherein R 3And R 4Each is alkyl naturally.
Another embodiment is the compound of formula (I), wherein R 3Be hydrogen, R 4It is alkyl.
Another embodiment is the compound of formula (I), wherein R 2And R 3The atom that is connected with them forms heterocycle.
Another embodiment is the compound of formula (I), wherein R 2And R 3The atom that is connected with them forms 5-unit heterocycle, R 4Be hydrogen; And represent by formula (II):
Figure 274598DEST_PATH_IMAGE025
(II),
Wherein
R 34And R 35Be hydrogen or alkyl independently; Or R 34And R 35The atom that is connected with them form naphthenic base and
R is 1 or 2.
Another embodiment is the compound of formula (I), wherein R 3And R 4The atom that is connected with them forms naphthenic base, heterocycle, heteroaryl or aryl.
Another embodiment is the compound of formula (I), wherein R 3And R 4The atom that is connected with them forms naphthenic base, heterocycle, heteroaryl or aryl; L is that key (that is, is-(CH as L 2) nIn-time, n is 0).
Another embodiment is the compound of formula (I), wherein R 3And R 4The atom that is connected with them forms naphthenic base or heterocycle.
Another embodiment is the compound of formula (I), wherein R 3And R 4The atom that is connected with them forms naphthenic base, and wherein naphthenic base is (C 3-C 6) naphthenic base.
Another embodiment is the compound of formula (I), wherein R 3And R 4The atom that is connected with them forms heteroaryl or aryl.
Another embodiment is the compound of formula (I), wherein R 4And R 5The atom that is connected with them forms naphthenic base or heterocycle.
Another embodiment is the compound of formula (I), wherein R 3Be hydrogen, R 4And R 5The atom that is connected with them forms naphthenic base or heterocycle.
Another embodiment is the compound of formula (I), wherein R 3Be hydrogen, R 4And R 5The atom that is connected with them forms heterocycle.
Another embodiment is the compound of formula (I), and wherein L is-(CR 38R 39) m-X-(CR 38R 39) n-or-(CR 38R 39) m-X-(CR 38R 39) n-Y-; Wherein m is 0, and X is-CR 36R 37-, R 36And R 2The atom that is connected with them forms heterocycle, and represents by formula (III) with (IV):
Figure 572855DEST_PATH_IMAGE026
Wherein s is 1 or 2 independently.
Another embodiment is the compound of formula (III), and wherein n is 0, R 5Be aryl or heteroaryl.
Another embodiment is the compound of formula (IV), wherein R 5Be aryl or heteroaryl.
Another embodiment is the compound of formula (I), and wherein L is-(CR 38R 39) m-X-(CR 38R 39) n-or-(CR 38R 39) m-X-(CR 38R 39) n-Y-; Wherein m is 0, and X is-NR 36-, R 36And R 2The atom that is connected with them forms heterocycle, and represents by formula (Va) with (Vb):
Figure 959974DEST_PATH_IMAGE027
Wherein t is 1 or 2.
Another embodiment is the compound of formula (I), wherein R 5Be amino, aryl, naphthenic base, heteroaryl or heterocycle.
Another embodiment is the compound of formula (I), wherein R 5Be naphthenic base, wherein this naphthenic base is optional is independently selected from following substituting group replacement by 1,2 or 3: alkoxyl group, alkyl, aryloxy, aryl; Carboxyl, carboxyalkyl, naphthenic base, cycloalkyloxy, halogen; Halogenated alkoxy, haloalkyl, halo thio alkoxy, heteroaryl; Hydroxyl, sulfydryl, thio alkoxy, sulfo-cycloalkyloxy and thio-aryloxy.
Another embodiment is the compound of formula (I), wherein R 5Be amino.
Another embodiment is the compound of formula (I), wherein R 5Be to choose wantonly to be independently selected from the substituted aryl of following substituting group: alkoxyl group, alkyl, aryloxy, carboxyl, carboxyalkyl by 1,2 or 3; Naphthenic base, cycloalkyloxy, cyanic acid, halogen; Halogenated alkoxy, haloalkyl, halo thio alkoxy, heteroaryl; Hydroxyl, sulfydryl, thio alkoxy, sulfo-cycloalkyloxy and thio-aryloxy.
Another embodiment is the compound of formula (I), wherein R 5Be to choose wantonly to be independently selected from the substituted phenyl of following substituting group: alkyl, cyanic acid, halogen, haloalkyl and heteroaryl by 1,2 or 3.
Another embodiment is the compound of formula (I), wherein R 5Be the heteroaryl that is selected from pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, wherein this heteroaryl is optional is independently selected from following substituting group replacement by 1,2 or 3: alkoxyl group, alkyl, aryl, aryloxy; Carboxyl, carboxyalkyl, naphthenic base, cycloalkyloxy, cyanic acid; Halogen, halogenated alkoxy, haloalkyl, halo thio alkoxy; Hydroxyl, sulfydryl, thio alkoxy, sulfo-cycloalkyloxy and thio-aryloxy.
Another embodiment is the compound of formula (I), wherein R 5Be pyridyl, wherein this pyridyl is optional is independently selected from following substituting group replacement by 1,2 or 3: alkyl, cyanic acid, halogen and haloalkyl.
Another embodiment is the compound of formula (I), wherein R 5Be to be selected from following heterocycle: azabicyclo [3.2.0] heptan-3-base, piperazinyl, piperidyl; Morpholinyl, the parathiazan base, wherein this heterocycle is optional is independently selected from following substituting group replacement by 1,2 or 3: alkoxyl group; Alkyl, aryl, cyanic acid; Halogen, haloalkyl and heteroaryl, wherein this aryl and heteroaryl are optional is replaced by halogen or haloalkyl.
Another embodiment is the compound of formula (I), wherein R 5It is the heterocycle that is selected from piperazinyl or piperidyl; Wherein this heterocycle is optional is independently selected from following substituting group replacement by 1,2 or 3: alkyl, aryl, cyanic acid; Halogen; Haloalkyl and heteroaryl, wherein this aryl is that phenyl and heteroaryl are pyridyl, and is optional separately by halogen or haloalkyl replacement.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) n-, wherein n is 0,1 or 2.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) n-, wherein n is 0.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) n-, wherein n is 1.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, n is 0.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, n is 1.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, n is 2.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 1, n is 0.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 1, n is 1.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 1, n is 2.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 2, n is 0.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 2, n is 1.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein m is 2, n is 2.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X is-O-.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X is-S-.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X be-S (O)-.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X is-S (O) 2-.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X is-NR 36-.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X is-CR 36R 37-.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X is-NR 36-; R wherein 36It is hydrogen or alkyl.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-, wherein X is-CR 36R 37-; R wherein 36And R 37Be hydrogen or alkyl independently.
Another embodiment is the compound of formula (I), and wherein L is that key (that is, is-(CH as L 2) nIn-time, n is 0), R 5Be amino.In further embodiment, R 5Be aryl or heteroaryl.In further embodiment, R 5It is heterocycle.
Another embodiment is the compound of formula (I), and wherein L is-(CH 2) m-X-(CH 2) n-Y-, wherein X is-CR 36R 37-, Y is O or NCH 3, n is 1, R 5Be aryl or heteroaryl.
Another embodiment is the compound of formula (I), and wherein W is N-CN.
Another embodiment is the compound of formula (I), and wherein W is S.
Another embodiment is the compound of formula (I), and wherein W is N-R 6, R wherein 6Be hydrogen, alkyl or aryl.
Another embodiment is the compound of formula (I), and wherein W is N-R 6, R wherein 6It is hydrogen or alkyl.
Another embodiment is the compound of formula (I), and wherein W is N-OR 6, R wherein 6Be hydrogen, alkyl or aryl.
Another embodiment is the compound of formula (I), and wherein W is N-OR 6, R wherein 6It is hydrogen or alkyl.
Another embodiment is the compound of formula (I), wherein R 1Be adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is methyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein two of m and n are 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is methyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein two of m and n are 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be optional by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, haloalkyl, cyanic acid, methoxyl group or haloalkyl, W is N-R 6, R 6Be hydrogen, L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0 or 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Two all is hydrogen, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from alkyl, halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) n-, wherein n is 1.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) n-, wherein n is 1.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be optional by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, R 6Be hydrogen, W is NR 6, L is-(CH 2) n-, wherein n is 1.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is methyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is hydrogen naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is hydrogen naturally, R 5Be to choose wantonly by the substituted pyridyl of halogen, W is N-CN, and L is-(CH 2) n-, wherein n is 1.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4It is (C that the atom that is connected with them combines 3-C 6) naphthenic base, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) n-, wherein n is 0.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4It is (C that the atom that is connected with them combines 3-C 6) naphthenic base, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted adamantyl (ii), R wherein 15Be hydrogen, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by halogen or the substituted heteroaryl of haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be to choose (ii) R wantonly by the substituted adamantyl of alkyl sulphonyl 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is S, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be to choose (ii) R wantonly by the substituted adamantyl of alkyl sulphonyl 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be optional by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, R 6Be alkyl, W is N-OR 6, L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be to choose (ii) R wantonly by the substituted adamantyl of alkyl sulphonyl 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be to choose (ii) R wantonly by the substituted adamantyl of alkyl sulphonyl 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by halogen or the substituted heteroaryl of haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-S (O) 2-N (R 32R 33) substituted adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-S (O) 2-N (R 32R 33) substituted adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, halogenated alkoxy, methoxyl group or haloalkyl, W is N-CN or S, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-S (O) 2-N (R 32R 33) substituted adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be optional by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-R 6, R 6Be hydrogen, L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0 or 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-S (O) 2-N (R 32R 33) substituted adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by halogen or the substituted heteroaryl of haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted adamantyl (ii), R wherein 18Be alkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, halogenated alkoxy, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted adamantyl (ii), R wherein 18Be alkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m and n each naturally 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted adamantyl (ii), R wherein 18Be alkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted adamantyl (ii), R wherein 18Be alkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is S, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted adamantyl (ii), R wherein 18Be alkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by the substituted heterocycle of heteroaryl (it is optional by the haloalkyl replacement), W is S, and L is-(CH 2) n-, wherein n is 0.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted adamantyl (ii), R wherein 18Be hydrogen, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted adamantyl (ii), R wherein 18Be alkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be heterocycle, W is N-CN, and L is-(CH 2) n-, wherein n is 0.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-C (O)-N (R 19R 20) substituted adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0 or 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-C (O)-N (R 19R 20) substituted adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be optional by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-R 6, R 6Be hydrogen, L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0 or 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-C (O)-N (R 19R 20) substituted adamantyl (ii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by halogen or the substituted heteroaryl of haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0 or 1, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be to choose (ii) R wantonly by the substituted adamantyl of cyanic acid 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be to choose (ii) R wantonly by the substituted adamantyl of cyanic acid 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by halogen or the substituted heteroaryl of haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be adamantyl (i), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CO 2R 18Substituted two ring [2.2.2] octyl groups (vi), R wherein 18Be hydrogen or alkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-C (O)-N (R 19R 20) substituted two ring [2.2.2] octyl group (vi), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional by substituted two ring [2.2.2] octyl group (vi), the R of cyanic acid 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-OR 15Substituted two ring [2.2.2] octyl groups (vi), R wherein 15Be hydrogen, alkyl or haloalkyl, R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CHF 2Substituted two ring [2.2.2] octyl group (vi), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be ring octyl group (v), R 2Be hydrogen, R 3And R 4Each is methyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein two of m and n are 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be outer (exo)-two ring [2.2.1] heptyl (xvi), R 2Be hydrogen, R 3And R 4Each is methyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein two of m and n are 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be octahydro-2,5-methylene radical pentalene base (xvii), R 2Be hydrogen, R 3And R 4Each is methyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein two of m and n are 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be 1-azabicyclo [2.2.2] octyl group (xvii), R 2Be hydrogen, R 3And R 4Each is methyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein two of m and n are 0, X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-C (O)-N (R 19R 20) substituted two ring [2.2.1] heptane-(viii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional by substituted two ring [2.2.1] heptane-(viii), the R of cyanic acid 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be optional quilt-CHF 2Substituted two ring [2.2.1] heptane-(viii), R 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
Another embodiment is the compound of formula (I), wherein R 1Be substituted two ring [2.2.1] heptane-(viii), the R of optional quilt-OH 2Be hydrogen, R 3And R 4Each is alkyl naturally, R 5Be to choose wantonly by 1 or 2 substituted phenyl of substituting group that is independently selected from halogen, cyanic acid, methoxyl group or haloalkyl, W is N-CN, and L is-(CH 2) m-X-(CH 2) n-, wherein m is 0, and n is 0, and X is O.
The exemplary compound of each embodiment including, but not limited to:
(1E)-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl third amidine (propanimidamide);
(1E)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-(2-aminomethyl phenyl) ethanamidine (ethanimidamide);
1-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] tetramethylene carbonamidine (carboximidamide);
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene base)-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-N'-cyanic acid-2-(2-fluorophenyl)-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-2-(2-chloro-pyridine-3-yl)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl-prop amidine;
2-(4-chlorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide;
(1E)-N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2 – methyl-prop imines acyl group] amino } diamantane-1-methyl-formiate;
2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide;
(1E)-2-(4-chlorophenoxy)-N'-methoxyl group-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine;
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
1-(3-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] the tetramethylene carbonamidine;
(E)-4-[(2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } sulfo-propionyl group (propanothioyl)) amino] diamantane-1-methyl-formiate;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate;
(1E)-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine;
N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy) phenoxy] thiopropionamide;
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the sulfo-propionyl group) amino] diamantane-1-methyl-formiate;
3-(4-chloro-phenyl-)-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine;
(1E)-3-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the sulfo-propionyl group) amino] diamantane-1-formic acid;
(1E)-N'-cyanic acid-N-[(E)-5-cyanic acid-2-adamantyl]-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third amidine;
(E)-4-((1E)-and N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
6-(4,4-dimethyl--1-[(E)-5-(methyl sulphonyl)-2-adamantyl]-5-sulfo-tetramethyleneimine-3-yl } methoxyl group) cigarette nitrile (nicotinonitrile);
(2Z)-and 4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--1-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] tetramethyleneimine-2-subunit cyanamide (cyanamide);
(3S)-1-[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl]-N-cyclohexyl piperidines-3-thioamides;
(3S)-1-[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl]-N'-cyanic acid-N-cyclohexyl piperidines-3-carbonamidine;
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-5-cyanic acid-2-adamantyl]-2-methyl-prop amidine;
(1E)-and 2-(4-chlorophenoxy)-N'-cyanic acid-N-six hydrogen-2,5-first bridge (methano) pentalene (pentalen)-3a (1H)-Ji-2-methyl-prop amidine;
(1E)-and N-[(4s)-1-aza-tricycle [3.3.1.1 3,7] last of the ten Heavenly stems-the 4-yl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-1-azabicyclo [2.2.2] oct-3-yl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-encircles octyl group-2-methyl-prop amidine;
N-[outer-two rings [2.2.1] heptan-2-yl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(1E)-N-1-adamantyl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine;
2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] thiopropionamide;
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine;
2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] thiopropionamide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-methane amides;
(E)-4-((1E)-2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate;
(E)-4-(2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-2-methyl sulfo-propionyl group } amino) diamantane-1-methyl-formiate;
(1E)-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-2-phenoxy third amidine;
(E)-4-{ [(1E)-and N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } diamantane-1-methane amide;
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
(1E)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-methyl-prop amidine;
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
N-[(outward)-two ring [2.2.1] heptan-2-yl]-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-methyl-prop amidine;
(1E)-N-(diamantane-1-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-encircles octyl group-2-methyl-prop amidine;
(1E)-N-[(E)-diamantane-2-yl]-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(E)-4-{ [(1E)-and 2-(4-chloro-2-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methyl-formiate;
(1E)-N'-cyanic acid-2-methyl-N-[(E)-5-(methyl sulphonyl) diamantane-2-yl]-2-phenoxy third amidine;
N'-cyanic acid-N-encircles octyl group-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
N-(outer-two rings [2.2.1] heptan-2-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-N-(six hydrogen-2,5-first bridge pentalene-3a (1H)-yl)-2-methyl-prop amidine;
(E)-4-{ [(1E)-and N-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
(1E)-N-[(3R, 5R)-diamantane-1-yl]-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
(1E)-N-(1-azabicyclo [2.2.2] oct-3-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-(six hydrogen-2,5-first bridge pentalene-3a (1H)-yl)-2-methyl-prop amidine;
(E)-4-{ [(1E)-and 2-(4-chloro-2-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
(E)-4-((1E)-and 2-[(5-chloro-pyridine-2-yl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
(E)-4-[(2-methyl-2-phenoxy tetrahydroform acyl group) amino] diamantane-1-methane amide;
(1E)-N'-cyanic acid-2-methyl-N-[(E)-5-(methyl sulphonyl) diamantane-2-yl]-2-(pyridine-2-base oxygen base) third amidine;
(1E)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-(2-fluorophenoxy)-2-methyl-prop amidine;
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.1] heptane-1-methane amides;
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.2] octane-1-methane amides;
N'-cyanic acid-N-(4-cyano-bicyclo [2.2.1] heptan-1-yl)-2-methyl-2-phenoxy third amidine;
N'-cyanic acid-N-(4-cyano-bicyclo [2.2.2] suffering-1-yl)-2-methyl-2-phenoxy third amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.2] suffering-1-yls]-2-methyl-prop amidine;
N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.2] suffering-1-yls]-2-methyl-2-phenoxy third amidine;
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.2] octane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.1] heptane-1-methane amides;
N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.1] heptan-1-yl]-2-methyl-2-phenoxy third amidine;
2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
2-(2-fluorophenoxy)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-2-phenoxy third amidine;
5-chloro-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-anisole carbonamidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(4-hydroxyl two ring [2.2.2] suffering-1-yls)-2-methyl-prop amidine;
N'-cyanic acid-N-(4-hydroxyl two ring [2.2.2] suffering-1-yls)-2-methyl-2-phenoxy third amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(4-cyano-bicyclo [2.2.2] suffering-1-yl)-2-methyl-prop amidine; With
N'-cyanic acid-N-(4-hydroxyl two ring [2.2.1] heptan-1-yl)-2-methyl-2-phenoxy third amidine.
Isomer
Compound of the present invention can exist with the stereoisomerism volume morphing, exists asymmetric therein or chiral centre.According to the substituent configuration around the chiral element, these steric isomers are " R " or " S " configurations.The term " R " that this paper uses and " S " be following in defined configuration: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl.Chem.,?1976,?45:?13-30。The present invention includes various steric isomers and its mixture, and comprise within the scope of the present invention particularly.Steric isomer comprises the mixture of enantiomorph and diastereomer and enantiomorph or diastereomer.The single stereoisomers of The compounds of this invention can synthesize preparation by the starting raw material that comprises asymmetric or chiral centre that is purchased, or is prepared by the method for the well-known fractionation of those of ordinary skills then through preparing racemic mixture.These method for splitting can illustrate through following: (1) makes the mixture of enantiomorph be connected with chiral auxiliary(reagent), utilizes recrystallization or chromatogram to come the mixture of the diastereomer of resulting separation, and optional from auxiliary agent, discharges optically pure product; As following said: Furniss, Hannaford, Smith; And Tatchell, " Vogel's Textbook of Practical Organic Chemistry ", 5th edition (1989); Longman Scientific & Technical, Essex CM20 2JE, England; Or (2) mixture of direct separation optically active enantiomorph on chiral chromatographic column, or (3) fractional recrystallization method.
Yet the right relative stereochemistry of enantiomorph is known sometimes, and absolute configuration is not known.In this case, use three-dimensional relatively chemical descriptor term " R* " and " S* ".Term " R* " and " S* ": Eliel that this paper uses have been defined in following, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons, Inc.:New York, 1994; Pp 119-120 and 1206.
The compound that comprises the geometrical isomer of the two keys of carbon-to-carbon double bond and carbon-nitrogen comprises in the present invention.Substituting group around the two keys of carbon-to-carbon or carbon-nitrogen is called Z or E configuration, and the substituting group around naphthenic base or the heterocycle is called cis or transconfiguration.All rotamerism forms of compound that this paper describes comprise within the scope of the present invention with its mixture.
The azepine of embodiment 39-diamantane part is not a chirality, yet thinks that the C-4 carbon that connects oxygen is pseudoasymmetric.According to the content described in following, the configuration ownership of the structure of amino azepine-diamantane part of embodiment 39 is appointed as 4s:Synthesis, 1992,1080, Becker, D. P.; Flynn, D.L. and Stereochemistry of Organic Compounds, E.L. Eliel, S.H Wilen; John Wiley and Sons, Inc. 1994.
The compound of isotopic enrichment or spike
Compound of the present invention can exist isotopic tracing or enriched form, and it comprises one or more atoms, and the nucleidic mass of this atom or total mass number are different from the nucleidic mass or the total mass number of the atom of occurring in nature maximum discovery.Isotropic substance can be radioactivity or inactive isotropic substance.Atom for example hydrogen, carbon, phosphorus, sulphur, fluorine, chlorine and iodine isotropic substance including, but not limited to: 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl with 125I.Other the isotopic compound that comprises these and/or other atom is within the scope of the invention.
In another embodiment, isotopically tagged compound comprise deuterium ( 2H), tritium ( 3H) or 14The C isotropic substance.The general method that isotopically tagged The compounds of this invention can utilize those of ordinary skills to know prepares.This isotopically tagged compound can be prepared as follows easily: carry out disclosed method in embodiment disclosed herein and the reaction scheme, substitute non-tracer reagent with the isotopic tracing reagent that obtains easily.In some cases, can use isotopic tracing agent treated compound, so that with its isotropic substance replacement normal atom, for example, at deuteric acid (D for example 2SO 4/ D 2O) under the effect, can replace hydrogen with deuterium.Except above-mentioned, for example, relevant method and midbody: Lizondo is also disclosed in following, people such as J, Drugs Fut, 21 (11), 1116 (1996); Brickner, people such as S J, J Med Chem, 39 (3), 673 (1996); Mallesham, people such as B, Org Lett, 5 (7), 963 (2003); The open WO1997010223 of PCT, WO2005099353, WO1995007271, WO2006008754; U.S. Pat 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; Disclose 20090137457 with U.S. Patent application; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; With 20090082471, this paper combines this method with the mode of quoting as proof.
Isotopically tagged The compounds of this invention can be used as the standard of the effect of measuring the 11-beta-HSD 1 inhibitors in combining test.In drug research, the mechanism of action and the pathways metabolism of the parent compound through estimating the heterotope spike, the internal metabolism home to return to of research compound (people such as Blake have been used to comprise isotopic compound J. Pharm. Sci.64,3,367-391 (1975)).In the design of medicine safely and effectively; This metabolism research is very important, and whether this is in order to prove the activity in vivo compound that gives the patient or to be toxic or carcinogens (people such as Foster, Advances in Drug Research Vol. 14 by the meta-bolites that parent compound produces; Pp. 2-36; Academic press, London, 1985; People such as Kato, J. Labelled Comp. Radiopharmaceut., 36 (10): 927-932 (1995); People such as Kushner, Can. J. Physiol. Pharmacol., 77,79-88 (1999).
In addition, comprise the medicine of non radioactive isotope, for example be called the deuterate medicine of " heavy medicine ", can be used to treat active relevant disease and illness with 11-β-HSD1.The isotopic amount among the compound of being present in is higher than its natural abundance and is known as enrichment.The example of the amount of enrichment comprises about 0.5,1,2,3,4,5,6,7,8,9,10,12,16,21,25,29,33,37,42,46,50,54,58,63,67,71,75,79,84,88,92,96 to about 100 mol%.Substituted about at the most 15% normal atom with heavy isotope; And in Mammals (comprising rodents and dog), keep several days time to several weeks; Observe minimum spinoff (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84:770; Thomson J F, Ann. New York Acad. Sci 1960 84:736; People such as Czakja D M, Am. J. Physiol. 1961 201:357).In people's body fluid; Substitute up to 15%-23% with deuterium is acute; Find can not cause toxicity (people in " Dosimetry & Treatment Planning for Neutron Capture Therapy " such as Blagojevic N; Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23:251 (1997)).
The medicine of stable isotopic tracer can change its physico-chemical property, for example pKa and lipid solubility.Influence the related zone of ligand-receptor interaction if isotropic substance replaces, these effects respond with the drug effect that variation can influence drug molecule so.Although some physicalies of stable isotopic tracer molecule are different with the physicals of labelled molecule not; But the chemistry and biology characteristic is identical; Important not being both: because the quality of heavy isotope increases, any key that relates to heavy isotope and another atom is stronger than the identical key between light isotope and this atom.Correspondingly,, introduce isotropic substance in the site of metabolism or enzymatic conversion and will slow down said reaction, possibly change pharmaco-kinetic properties or effect with respect to the heterotope compound.
Acid amides, ester and prodrug
Prodrug is the verivate of active medicine, is used for improving that some are confirmed, undesirable physics or biological property.Physicals is solubleness (too high insufficient lipid or water-soluble) or relevant stability normally, and problematic biological characteristics comprises the bioavailability of metabolism too fast or difference, and itself maybe be relevant with physicochemical property.
Prodrug is prepared as follows usually: the ester, half ester, carbonic ether, nitric ether, acid amides, hydroxamic acid, carbamate, imines, Mannich base and the enamine that a) form active medicine; B) with azo, glucosides, peptide and ether functional group with pharmic functionization, c) make polymkeric substance, salt, mixture, phosphoramide, acetal, semi-acetal and the ketal form of medicament.For example; Referring to Andrejus Korolkovas`s, " Essentials of Medicinal Chemistry ", John Wiley-Interscience Publications; John Wiley and Sons; New York (1988), pp. 97-118, this paper combines its full content with the mode of quoting as proof.
Ester can utilize general method well known by persons skilled in the art, prepared by the substrate of the formula that comprises hydroxyl or carboxyl (I).The type reaction of these compounds is to substitute a heteroatomic replacement with another atom, for example:
Reaction scheme 1
Figure 329776DEST_PATH_IMAGE028
Acid amides can be with similar form, prepared by the substrate of the formula that comprises amino or carboxyl (I).Ester can also with amine or ammonia react, form acid amides.
Reaction scheme 2
Figure 158054DEST_PATH_IMAGE029
Another method by the compound acid amides of formula (I) is that carboxylic acid and amine are heated together.
Reaction scheme 3
Figure 955109DEST_PATH_IMAGE030
In reaction scheme 2 and 3, R and R' are substrate, alkyl or the hydrogen of formula (I) independently.The various embodiments that are used for the formula (I) of the substrate of prodrug and ester include but not limited to: embodiment 1,2, and 3,4,5,6,7,8,15,22,23,24,26,30,46,49,51,55,58,80,87 and 91.Embodiment 11,16,17,21,28,29,48 and 63 representational esters of the present invention.Embodiment 14,25,31,47,50,70,74,75,76,81,82 and 88 representational acid amides of the present invention.
Compsn of the present invention
The present invention also provides pharmaceutical composition, and the compound that in compsn, comprises the formula (I) of treating significant quantity combines with pharmaceutically acceptable carrier.
Pharmaceutical composition of the present invention is administration of human and other Mammals in the following manner: oral, and rectum, parenteral, in the brain pond, intravaginal, intraperitoneal, local (for example, pulvis, ointment or drops) is through cheek or oral cavity or nasal spray.
The pharmaceutical composition that is used for parenteral injection comprises pharmaceutically acceptable sterilized water or non-aqueous solution, dispersion-s, suspension-s or emulsion and is used to be reassembled as the sterile powder of aseptic injectable solution or dispersion-s.The example of suitable water and nonaqueous carrier, thinner, solvent or vehicle comprises water, ethanol, polyvalent alcohol (Ucar 35; Polyoxyethylene glycol; USP Kosher, or the like and its suitable mixture), vegetables oil (for example sweet oil) and injection organic ester (for example OE) or its suitable mixture.Through utilizing dressing (for example Yelkin TTS),,, can keep the proper flow of compsn through utilizing tensio-active agent through keeping the particle diameter of desired dispersion-s.
These compsns can also comprise adjuvant, for example sanitas, wetting agent, emulsifying agent and dispersion agent.Utilize various antibiotic and anti-mycotic agents, for example, p-hydroxybenzoic acid, butylene-chlorohydrin, phenol, Sorbic Acid, or the like, can guarantee to prevent action of microorganisms.Comprise etc. that to ooze reagent (for example, sugar, sodium-chlor or the like) also can be desirable.Through utilizing the reagent of delayed absorption, for example, aluminum monostearate and gelatin can cause the prolongation of injectable drug form to absorb.
In some cases, for the effect of prolong drug, the absorption that slows down subcutaneous or intramuscularly medicine usually is desirable.This can realize through the crystal of use water-soluble difference or the liquid suspension of amorphous substance.The uptake rate of medicine can depend on its dissolution rate, thereby it can depend on crystallographic dimension and crystallized form.Perhaps, parenteral administered agents form can be through with medicine dissolution or be suspended in the oily vehicle and give.
Except active compound, suspensoid can also comprise suspension agent, for example, and the isooctadecane of ethoxylation alcohol, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, white lake, wilkinite, agar, tragacanth and its mixture partially.
If necessary, for more effective distribution, compound of the present invention can be incorporated into slowly-releasing or targeted delivery systems, for example polymeric matrix, liposome and microsphere.
In biodegradable polymkeric substance (for example polylactide-gather NSC 403079), prepare injection depot formulations (depot) form through the micro-encapsulated matrix that forms medicine.According to the ratio of medicine and polymkeric substance and the character of the concrete polymkeric substance that uses, can control drug release speed.The example of other biodegradable polymkeric substance comprises and gathers (ortho ester) and gather (acid anhydrides).Long acting injection also can prepare through medicine being collected in liposome or the microemulsion (it is compatible with bodily tissue).
Can injection formulations be sterilized, for example, filter, or add the sterilant of aseptic solid composite form through the strainer that holds bacterium, can be just before using with its dissolving be dispersed in sterilized water or other aseptic injection medium in.
Injection formulations (for example, aseptic injection water or oil suspension) can be according to known technique, use suitable dispersion agent or wetting agent and suspension agent to prepare.Aseptic injection preparation also can be aseptic injectable solution, suspension-s or emulsion (in nontoxic, parenteral acceptable diluent or solvent, for example the solution in 1,3 butylene glycol).Among operable acceptable vehicle and solvent, can make water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic expressed oil is usually as solvent or suspension medium.For this purpose, can use any soft expressed oil, comprise synthetic monoglyceride or triglyceride.In addition, in injection formulations, use lipid acid, for example oleic acid.
Oral dosage form comprises capsule, tablet, pill, pulvis and granule.In this solid dosage, with one or more compound of the present invention and at least a inertia pharmaceutically acceptable carrier (for example Sodium Citrate or secondary calcium phosphate) and/or following the mixing: a) filler or swelling agent, for example starch; Lactose; Sucrose, glucose, mannitol and Whitfield's ointment; B) tackiness agent, Cellulose,ether with glycolic acid for example, alginates, gelatin, Vinylpyrrolidone polymer, sucrose and gum arabic; C) wetting agent, for example USP Kosher; D) disintegrating agent, agar for example, lime carbonate, yam or tapioca(flour), Lalgine, some silicate and yellow soda ash; E) dissolving retarding agent, for example paraffinic hydrocarbon; F) absorption enhancer, for example quaternary ammonium compound; G) wetting agent, for example Tego Alkanol 16 and glyceryl monostearate; H) sorbent material, for example kaolin and wilkinite; And i) lubricant, for example talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium laurylsulfonate and its mixture.Under the situation of capsule, tablet and pill, formulation can also comprise buffer reagent.
The solids compsn of similar type also can be used as filler in the gelatine capsule (using lactose or toffee and high molecular weight polyethylene glycol) of soft hard filling.
The solid dosage of tablet, lozenge, capsule, pill and granule can be used dressing and shell preparation, for example well-known other dressing in enteric coating and the medicine formulation art.They can be chosen wantonly and comprise opalizer, and can be to delay the compsn that mode discharges active ingredient only or in certain part of enteron aisle.The examples of material that can be used for delaying release bioactive agent can comprise polymkeric substance and paraffin.
The liquid oral formulation comprises pharmaceutical acceptable emulsion, microemulsion, solution, suspensoid, syrup and elixir.Except active compound, liquid dosage form can also comprise the normally used inert diluent in this area, for example, and water or other solvent, solubilizing agent and emulsifying agent; Ethanol for example, Virahol, ethyl-carbonate, ETHYLE ACETATE, phenylcarbinol; Peruscabin, Ucar 35,1,3 butylene glycol, N; Oil (especially cottonseed, Semen arachidis hypogaeae, corn, plumule, olive, castor-oil plant and til), USP Kosher, tetrahydrofurfuryl alcohol, the fatty ester of polyoxyethylene glycol and sorbitan and its mixture.
Except inert diluent, oral compsns can also comprise adjuvant, for example wetting agent, emulsification and suspension agent, sweeting agent, seasonings and perfume compound.
The part of The compounds of this invention or transdermal administration formulation comprise ointment, paste, ointment, lotion, gelifying agent, pulvis, solution, sprays, inhalation or paster.Under aseptic condition, with the sanitas or the buffer of needed The compounds of this invention and pharmaceutically acceptable carrier and any needs.Eyes preparation, ear dropping liquid, eye ointment, pulvis and solution are also included within the scope of the invention.
Except active compound of the present invention, ointment, paste, ointment and gelifying agent can also comprise animal and vegetables fat, oil, paraffin, paraffinic hydrocarbon; Starch, tragacanth, derivatived cellulose, polyoxyethylene glycol; Siloxanes, wilkinite, silicic acid, talcum powder and zinc oxide or its mixture.
Except compound of the present invention, pulvis and sprays can also comprise lactose, talcum powder, silicic acid, white lake, the mixture of Calucium Silicate powder and polyamide powder or these materials.Sprays can also comprise common casting charge, for example CFCs.
Also can give compound of the present invention and compsn with the liposome form.As known in the art, liposome is usually derived from phosphatide or other lipid matter.Liposome is formed by the list or the multilayer aqua liquid crystalline substance that are dispersed in the water medium.Can use can form liposome any nontoxic, physiology is acceptable and metabolizable lipid.Except compound of the present invention, the present composition of liposome form can also comprise stablizer, sanitas or the like.In one embodiment of the invention, lipid is natural and synthetic phosphatide and the cholinphospholipide (Yelkin TTS) that separately or together uses.In this area, the method that forms liposome is known.Referring to, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), and p 33 et seq., this paper combines its content with the mode of quoting as proof.
The topical formulation of The compounds of this invention comprises pulvis, sprays, ointment and inhalation.Under aseptic condition, active compound is mixed with sanitas, buffer reagent or the casting charge of pharmaceutically acceptable carrier and any needs.Eyes preparation, eye ointment, pulvis and solution also design and are included within the scope of the invention.Aqueous liquid composition of the present invention is especially effective.
In another embodiment of the invention; Rectum or vagina administration compsn are suppository, and it can be prepared as follows: compound of the present invention is mixed with suitable non-irritating carrier, for example theobroma oil, polyoxyethylene glycol or suppository paraffin; It is solid at ambient temperature; But under body temperature, be liquid, therefore can in rectum or vaginal canal, melt, and release of active compounds.
Compsn comprise significant quantity, with the The compounds of this invention of the suitable vehicle of one or more treatment preparation.The example of treating suitable vehicle is including, but not limited to sugar, Mierocrystalline cellulose and their verivate, and oil, glycol, solution, buffer reagent, tinting material, release agent, the coating agent, sweeting agent, seasonings, perfume compound, or the like.
The effective dose of employed active ingredient can change according to employed particular compound, mode of administration, the illness of being treated and sanatory severity.Those skilled in the art can easily confirm this dosage.
When treatment or preventive (I) disease that compound was directed against; Usually with every kilogram of the weight of animals about 0.1 milligram when giving The compounds of this invention to about 100 milligrams per daily dose; Usually can obtain gratifying effect; Preferably, with single per daily dose or every day two to six times separate doses form administration, or with the sustained release form administration.For most of Mammalss, total per daily dose is about 1.0 milligrams to about 1000 milligrams, and is preferred, about 1 milligram to about 50 milligrams.Under the adult situation of 70 kg, normally about 7 milligrams to about 350 milligrams of total per daily dose.Can regulate this dosage regimen, so that the optimal treatment response is provided.
Method of the present invention
Glucocorticosteroid is in very wide tissue and organ scope, to regulate the steroid hormone that plays an important role in the multiple physiological processes.For example, glucocorticosteroid is effective regulator of glucose and lipid metabolism.Excessive glucocorticosteroid effect can cause insulin resistant, type ii diabetes, hyperlipemia, internal organ obesity and vascular hypertension.At philtrum, hydrocortisone and Kendall compound are respectively the main activity and the inactive form of glucocorticosteroid, and Kendall compound and dehydrocorticosterone are main activity and inactive form in rodents.
Through combining of glucocorticosteroid and acceptor (for example GR and mineralcorticoid receptor), cause the glucocorticosteroid effect.Through with its receptors bind, main mineralocorticoid aldosterone is controlled at the intravital fluid and electrolyte balance of body.Yet mineralcorticoid receptor all has high affinity for hydrocortisone and aldosterone.
Though hydrocortisone be important and generally acknowledged antiphlogistic (J. Baxer, Pharmac. Ther., 2,605-659 (1976)), if but have a large amount of quantity, also have disadvantageous effect.For example, hydrocortisone has the effect of synalbumin in liver, causes insulin sensitivity to reduce, and increases gluconeogenesis.Therefore, in the presence of unusual high-caliber hydrocortisone, the patient who has suffered from glucose tolerance weakening has the bigger probability that forms type ii diabetes.
Because glucocorticosteroid is the effective regulator of glucose and lipid metabolism, the effect of over-drastic glucocorticosteroid can cause insulin resistant, type ii diabetes, hyperlipemia, internal organ obesity and vascular hypertension.The present invention relates to treat 11 beta-HSD 1 inhibitors of effective dose, be used to treat, control, improve by the excessive of hydrocortisone and/or other corticosteroid or do not have and control quantity or active disease and illness that is mediated and/or the outbreak that delays them.Suppressing 11 β-HSD1 enzyme can limit nonactive Kendall compound and be converted into active hydrocortisone.If there is excessive quantity, hydrocortisone can cause or facilitate the symptom of these diseases and illness.
The dysregulation and the Metabolic disorder of glucocorticoid activity have relation, comprise type ii diabetes, metabolic syndrome, Cushing's syndromes, Addison disease and other disease.Glucocorticosteroid raises the crucial gluconeogenic enzyme in the liver; For example phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase); Therefore, be expected at and reduce local glucocorticosteroid level in this tissue, can improve the glucose metabolism of type ii diabetes.11 β-HSD1 acceptor whole body reject mouse and in grease, cross the mouse of expressing 11 β-HSD2 (causing the level of the active glucocorticosteroid in the grease to reduce) than their wild-type obverse have better glucose controllability (people such as Masuzaki, Science, 294,2166-2170 (2001); People such as Harris, Endocrinology,142,114-120 (2001); People such as Kershaw, Diabetes,54,1023-1031 (2005)).Therefore, specificity 11 beta-HSD 1 inhibitors can be used for treatment or prevention type ii diabetes and/or insulin resistant.
Through reducing insulin resistant and keeping serum glucose in normal concentration; Compound of the present invention usually also can have applicability in the many illnesss with type ii diabetes and insulin resistant in treatment and prevention; Comprise metabolic syndrome; Obesity, reactive hypoglycemia and diabetic hyperlipemia.Following disease, obstacle and illness relate to type ii diabetes, and can be through can treat, control, prevent and/or delay their outbreak to them with The compounds of this invention treatment: hyperglycemia, low glucose tolerance, insulin resistant, obesity; Lipid metabolism disorders, hyperlipemia, hyperlipidemia, hypertriglyceridemia; Hypercholesterolemia, low HDL levels, high LDL level, atherosclerosis and its sequela; Vascular restenosis, pancreatitis, the abdomen position is fat, neurodegenerative disease; Retinopathy, ephrosis, neuropathy, metabolic syndrome and insulin resistant are other illnesss of integral part.
The abdomen position fat with glucose intolerance (people such as Montaque; Diabetes, 49,883-888 (2000)), hyperinsulinemia, hypertriglyceridemia and metabolic syndrome (also claiming syndrome X) are (for example; Hypertension, LDL raises and the HDL reduction) other factors closely related.A large amount of animal datas is supported the effect of HSD1 in the nosogenesis of metabolic syndrome.(people such as Masuzaki, Science,294,2166-2170 (2001); People such as Paterson, Proc Natl. Acad. Sci. USA, 101,7088-93, (2004); People such as Montague, Diabetes,49,883-888 (2000)).Thus, 11 beta-HSD 1 inhibitors that give significant quantity can be used for treatment or control metabolic syndrome.In addition, be independent of the treatment of 11 beta-HSD 1 inhibitors or the effect of prophylactic treatment NIDDM (NIDDM),, give 11 beta-HSD 1 inhibitors and can be used for treatment or controlling obesity disease through controlling excessive hydrocortisone.If the patient uses 11 beta-HSD 1 inhibitors and the combination of keeping on a diet and taking exercise, also can be effective to delay the outbreak of obesity with 11 beta-HSD 1 inhibitors long-term treatments, or can fully prevent it.Effective as selective 11 beta-HSD 1 inhibitors also should have therapeutic value in the treatment of glucocorticosteroid relative influence or any following associated conditions that with the metabolic syndrome is characteristic: hyperglycemia, low glucose tolerance, insulin resistant, obesity; The lipid obstacle, hyperlipemia, hyperlipidemia, HTC; Hypercholesterolemia, low HDL levels, high LDL level, atherosclerosis; Vascular restenosis, pancreatitis, obesity, neurodegenerative disease; Retinopathy, ephrosis, hepatic steatosis or relevant hepatic diseases and syndrome X, and insulin resistant is other obstacle of integral part.
11 β-HSD1 expresses in islet cells (pancreatic islet cells), the insulin secretion that wherein active glucocorticosteroid stimulates glucose have negative effects (people such as Davani, Biol. Chem., 10,34841-34844 (2000); People such as Tadayyon, Expert Opin. Investig. Drugs,12,307-324 (2003); People such as Billaudel, J. Endocrinol.,95,315-20 (1982)).It is reported that dehydrocorticosterone is converted into Kendall compound (through 11 β-HSD1) can suppress Regular Insulin from isolating mouse pancreas beta cell, to secrete.Pancreas islet with 11 beta-HSD 1 inhibitors culture of isolated can increase the insulin secretion that glucose stimulates.Previous research explanation glucocorticosteroid can reduce insulin secretion in the body (people such as B. Billaudel, Horm. Metab. Res., 11,555-560 (1979)), therefore, in pancreas, suppressing 11 β-HSD1 enzyme can increase the Regular Insulin release that glucose stimulates.
Glucocorticosteroid can combine with GR (with possible mineralcorticoid receptor) and with its activation, thus strengthen catecholamine and Angiotensin II the two the vasoconstriction effect (people such as Pirpiris, Hypertension, 19,567-574 (1992); People such as Kornel, Steroids, 58,580-587 (1993): people such as Walker, Clin. Sci., 82,597-605 (1992)).11 β-HSD1 enzyme is present in the vascular smooth muscle, thinks that it can control systole response with 11 β-HSD2.In having the tissue of mineralcorticoid receptor, there is high-caliber hydrocortisone, can causes vascular hypertension.Therefore, effectively treatment or prophylactic treatment, control and improve the symptom of vascular hypertension of 11 beta-HSD 1 inhibitors that give therapeutic dose.
The Cushing's syndromes is life-threatening metabolic disease; It is a characteristic with long-term rising of glucocorticosteroid level; This glucocorticosteroid level raises and results from from suprarenal gland endogenous and produce excessive hydrocortisone and cause, or results from the exogenous glucocorticosteroid (for example prednisone or DEXAMETHASONE BP98) (as the part of anti-inflammatory therapy scheme) that gives high dosage.Typical C ushingoid characteristic comprises central obesity, mellitus and/or insulin resistant, hyperlipemia; Vascular hypertension, cognitive ability reduces, dementia; Osteoporosis, atherosclerosis, moon-face; Buffalo hump, thinning of skin and insomnia, other characteristic (Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth Becker in addition; Lippincott Williams and Wilkins Publishers, Philadelphia, 723-8 (2001)).Therefore, expectation effective as selective 11 beta-HSD 1 inhibitors can be effective to treat the Cushing's disease.
In the patient who suffers from the Cushing's syndromes, also observe the effect that cortisol levels raises (people such as Orth, J. Med., 332,791-803 (1995); People such as Boscaro, Lancet, 357,783-791 (2001); People such as Bertagna, Cushing ' s Disease, In:Melmed, Ed., The Pituitary, 2 NdEd. Blackwell, 592-612 (2002), it is to be characteristic with high-caliber hydrocortisone in the blood.The patient who suffers from the Cushing's syndromes usually forms the symptom of many type ii diabetes, obesity, metabolic syndromes and hyperlipemia, comprises insulin resistant, central obesity, and vascular hypertension, glucose intolerance, or the like.
As stated, 11 beta-HSD 1 inhibitors can effectively be treated many characteristics of metabolic syndromes, comprise vascular hypertension and hyperlipemia.The combination of vascular hypertension and hyperlipemia helps to form atherosclerosis; Therefore people's expectation, 11 beta-HSD 1 inhibitors of treating significant quantity can treat, control the atherosclerosis and other metabolic syndromes that come from cardiovascular disorder, delay their outbreak and/or it is prevented.
With a local pronounced side effects relevant with system's glucocorticoid treatment is the glaucoma that corticosteroid causes.This illness causes intraocular pressure seriously to improve, can be potential causes losing one's sight (people such as Armaly, Arch Ophthalmol,78,193-7 (1967); People such as Stokes, Invest Ophthalmol Vis Sci., 44,5163-7 (2003)).The cell that in eyes, produces most of aqueous humor is non-pigmented epithelial cell (NPE).Verified these cells can be expressed 11 β-HSD1, and are consistent with the expression of 11 β-HSD1, and find the hydrocortisone in the aqueous humor: the ratio of Kendall compound raise (people such as Rauz, Invest Ophthalmol Vis Sci., 42,2037-2042 (2001)).In addition, show, with respect to suffering from glaucoma but do not absorb the Kendall compound in patient's aqueous humor of exogenous steroidal, have rising cortisol levels (people such as Rauz, QJM,96,481-490 (2003)).With non-selective 11 β-HSD1 and 11 β-HSD2 suppressor factor carbenoxolone treatment patient 4 with 7 days, can make intraocular pressure reduce by 10% and 17% significantly respectively, and the local hydrocortisone generation of reduction in eyes (people such as Rauz, QJM,96,481-490 (2003)).Therefore, give 11 β-HSD1 special inhibitor and can be used to treat glaucoma.
In some morbid state, for example pulmonary tuberculosis, psoriasis and stress response, in the time in fact can more being of value to the patient based on the response of cell, high glucocorticoid activity changes the immunne response to the body fluid response usually.Suppress 11 β-HSD1 activity and can reduce the glucocorticosteroid level, change thus to based on the immunne response of the response of cell (Mason, Immunology Today, 12,57-60 (1991); Rook, Baillier ' s Clin. Endocrinol. Metab., 13,576-581 (1999)).Therefore, give 11 β-HSD1 specific inhibitor and can be used to treat disease or the illness that pulmonary tuberculosis, psoriasis, stress response and high glucocorticoid activity change the immunne response that body fluid is responded usually.
The known sugars cortin can cause the relevant spinoff of various skins, comprise thinning of skin and wound healing defective (Anstead, Adv Wound Care,11,277-85 (1998); People such as Beer, Vitam Horm., 59,217-39 (2000)).11 β-HSD1 expresses in the human skin fibroblast; And in the test of skin heart shrinking agent, show; Carry out the usefulness (people such as Hammami that topical therapeutic can improve the local HYDROCORTISONE INJECTIONS that uses with nonselective 11 β-HSD1 and 11 β-HSD2 suppressor factor Potenlini J. Clin. Endocrinol. Metab., 73,326-34 (1991)).The advantageous effects (International Publication WO 2004/11310) of selectivity 11 beta-HSD 1 inhibitors to wound healing also disclosed.Therefore, expectation effective as selective 11 beta-HSD 1 inhibitors can be treated because excessive wound healing that glucocorticoid activity caused or thinning of skin.
Excessive glucocorticosteroid can reduce the bone mineral density, and increases risk of fractures.This effect mainly mediates through being suppressed to the osteocyte bone forming, cause os purum matter forfeiture (people such as Kim, J. Endocrinol., 162,371-379 (1999); People such as Bellows, Bone, 23,119-125 (1998); People such as Cooper, Bone, 27,375-381 (2000)).Also the known sugars cortin can in Mammals, increase bone resorption with reduce bone forming (people such as Turner, Calcif. Tissue Int., 54,311-5 (1995); People such as Lane, Med. Pediatr. Oncol., 41,212-6 (2003)).Shown in human osteoblast cell's in people's bone homogenate the primary culture that 11 β-HSD1 mRNA express and reductase activity (people such as Bland, J. Endocrinol., 161,455-464 (1999); People such as Cooper, Bone, 23,119-125 (2000); People such as Cooper, J. Bone Miner. Res.,17,979-986 (2002)).In the explant of the operation that from Cosmetics Surgery, obtains, between young and old donor, find the expression of 11 β-HSD1 in osteoblastic primary culture improved about 3 times (people such as Cooper, J. Bone Miner. Res.,17,979-986 (2002)).Glucocorticosteroid (for example prednisone and DEXAMETHASONE BP98) also is used to treat various inflammatory conditions usually, comprises sacroiliitis, inflammatory bowel and asthma.These steroidal medicaments be illustrated among the human osteoblast cell expression that improves 11 β-HSD1 mRNA and activity (people such as Cooper, J. Bone Miner. Res.,17,979-986 (2002)).In original scleroblast and MG-63 osteosarcoma cell, shown similar result, wherein struvite cytokine TNF α and IL-1 β improve 11 β-HSD1 mRNA express with activity (people such as Cooper, J. Bone Miner. Res.,16,1037-1044 (2001)).These study explanation, because excessive glucocorticosteroid level or active result, in the process that the unfavorable situation that bone photo closes forms, 11 β-HSD1 plays the potential vital role.The bone sample of taking from healthy subjects volunteer (oral non-selective 11 β-HSD1 and 11 β-HSD2 suppressor factor carbenoxolone) shown the remarkable reduction of bone resorption affinity tag (people such as Cooper, Bone,27,375-81 (2000)).Therefore, giving 11 β-HSD1 specific inhibitor can be used for preventing owing to glucocorticosteroid bone forfeiture that cause or that dependent osteoporosis of age is caused.
Research shows, in the homogenate of hippocampus, occur dehydrogenation and reduction (people such as Lakshmi, Endocrinol, 128,1741-1748 (1991)), and in mammal brain, express 11 β-HSD1, disclosed data show, glucocorticosteroid can cause neuronal degeneration and dysfunction (people such as de Quervain, Hum Mol Genet., 13,47-52 (2004); People such as Belanoff, J. Psychiatr. Res., 35,127-35 (2001)).Some researchs have shown that 11 β in the hippocampal neuron-HSD are active, immunoreactivity and mRNA express (people such as Moisan, Endocrinol,127,1450-1455 (1990); People such as Lakshmi, Endocrinol, 128,1741-1748 (1991); People such as Sakai, J. Neuroendocrinol., 4,101-106 (1992)).Give 11 β-HSD suppressor factor can in hippocampus, change in the body functionally active (people such as Seckl, J. Endocrinol.,136,471-477 (1993)).In the evidence explanation of rodents and philtrum, the long-term rising of blood plasma glucocorticosteroid level can make cognitive function weaken, and this weakening becomes more serious along with aging (People such as Issa, J. Neurosci., 10,3247-3254 (1990); People such as Lupien, Nat. Neurosci., 1,69-73 (1998): people such as Yau, Neuroscience, 66,571-581 (1995)).Long-term excessive cortisol levels in the brain can cause neurone forfeiture and neuron dysfunction (people such as Kerr, Psychobiology,22,123-133 (1994); Woolley, Brain Res., 531,225-231 (1990); Landfield, Science, 272,1249-1251 (1996)).In addition, the acute mental disorder that glucocorticosteroid causes has been explained the more pharmacology inducing action of this response, and when with these steroidal pharmaceutical treatments patients, its be the problem mainly considered of doctor (people such as Wolkowitz, Ann NY Acad Sci., 1032,191-4 (2004)).People such as Thekkapat are verified; 11 β-HSD1 mRNA expresses in people hippocampus, volume side cortex and cerebellum; And, can improve fluency and the memory (people such as Thekkapat of speech with nonselective 11 β-HSD1 and 11 β-HSD2 suppressor factor carbenoxolone treatment sensile diabetic patient Proc Natl Acad Sci USA. 101,6743-9 (2004)).In addition, people such as Walker have checked 11 β-HSD active and its function (U.S. Pat 7,122,531 in the primary culture of fetus hippocampal cell; U.S. Pat 7,087,400; People such as Rajan, J. Neurosci., 16,65-70 (1996)).
Therefore, can be through treating, control, prevent with The compounds of this invention or delaying CNS disease, obstacle and illness.11 beta-HSD 1 inhibitors that give therapeutic dose can reduce, improve, control and/or prevent illness, for example general stress response, neurodegeneration, the cognitive defect relevant with aging; Neuron dysfunction, dementia, the acute mental disorder that steroidal causes, cognitive function decline and relevant dementia in the Alzheimer disease; With the old and feeble cognitive defect relevant with neurodegeneration, dementia, senile dementia, AIDS is dull-witted; Melancholia, severe depression obstacle, psychotic depression, intractable melancholia; Anxiety, panic disorder, post-traumatic nervous sexual dysfunction, the cognitive function decline in the Cushing's syndromes; The acute mental disorder that melancholia in the Cushing's syndromes, steroidal cause, the cognitive defect relevant, general attention deficit disorder with mellitus; Attention deficit superfunction obstacle (ADHD), acute mental disorder that slight cognitive defect, steroidal cause and schizophrenia.
Correspondingly, an embodiment is to suppress the method for 11 β-HSD1, and this method comprises: the compound that gives the formula (I) of Mammals treatment significant quantity.Another embodiment is treatment or the mammiferous above-mentioned illness of prophylactic treatment.In Mammals, this illness can be by excessive glucocorticosteroid effect mediation.
Another embodiment is sanatory method, including, but not limited to: Cushing's syndromes, non-insulin-dependent type ii diabetes, insulin resistant, obesity, lipid metabolism disorders (hyperlipemia); The metabolic syndromes, hyperglycemia, low glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia; Low HDL levels, high LDL level, atherosclerosis and its sequela, vascular restenosis, pancreatitis, abdomen position obesity; Retinopathy, ephrosis (nephropather), neuropathy, vascular hypertension, insulin resistant is other illness of integral part; Glaucoma, sacroiliitis, osteoporosis, neuron dysfunction, neurodegeneration; The cognitive defect relevant with aging, dementia, alzheimer's disease, cognitive function decline and relevant dementia in the alzheimer's disease are with the old and feeble cognitive defect relevant with neurodegeneration; Dementia, senile dementia, AIDS is dull-witted, anxiety, panic disorder; Post-traumatic nervous sexual dysfunction, the acute mental disorder that steroidal causes, the cognitive defect relevant, general attention deficit illness, the hyperfunction illness of attention deficit sexual function (ADHD) with mellitus; Slight cognitive defect, the cognitive function decline in the Cushing's syndromes, schizophrenia, melancholia, severe depression illness; Psychotic depression, the melancholia in the Cushing's syndromes, intractable melancholia, the acute mental disorder that steroidal causes, and other disease relevant with hydrocortisone or glucocorticosteroid.
Another embodiment provides the method for treatment patient's alzheimer's disease, and therefore reduces S&S.
In order to treat neurodegeneration or neuropsychiatric illness, this method comprises: the described herein any compound or pharmaceutically acceptable salt thereof that needs patient (for example, Mammals, for example people) the treatment significant quantity of this treatment.Perhaps, this method comprises: give the described herein any compound or pharmaceutically acceptable salt thereof of patient treatment significant quantity and at least a cognitive combination that improves medicine of treatment significant quantity." the cognitive medicine that improves " of this paper definition is the medicine of the impaired cognitive ability (thinking just, learning and memory) of improving human brain.Cognitive improve the utilization ratio of medicine through changing neurochemical (for example, neurotransmitter, enzyme and hormone), increase oxygen supply, the growth or suppress nerve injury and work of exciting nerve.The cognitive example that improves medicine comprises: improve the active compound of vagusstoff, such as, but be not limited to: acetyl choline receptor agonists (for example, nicotine alpha-7 receptor agonist or allosteric modulators; α 4 β, 2 nicotinic receptor agonists or allosteric modulators), acetylcholinesterase depressant (for example, E2020; Bright and the lycoremine (galantamine) of Li Fansi), butyrylcholinesterase inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonist is (for example; U.S. dollar amine (Memantine)), activity-dependency neuroprotective albumen (ADNP) agonist, thrombotonin 5-HT1A receptor stimulant is (for example; Xaliproden (xaliproden)), 5-HT 4Receptor stimulant, 5-HT 6Receptor antagonist, thrombotonin 1A receptor antagonist, histamine H 3Receptor antagonist, calpain inhibitor, VEGF (VEGF) albumen or agonist, the factor of nourishing and growing; Anti-apoptosis compound, AMPA type glutamate receptor acvator, L type or N type calcium channel blocker or regulator, potassium channel blocker; Hypoxia inducible factor (HIF) acvator, HIF prolyl 4-hydroxylase inhibitors, antiphlogistic, the suppressor factor of amyloid A β peptide or amyloid patch; The suppressor factor of tau peroxophosphoric acidization, phosphodiesterase 5 suppressor factor (for example Tadalafei (tadalafil), Virga); Phosphodiesterase 4 inhibitors, oxidase inhibitor, or its pharmacologically acceptable salt.This cognitive object lesson that improves medicine is including, but not limited to anticholinesterase, for example E2020 (Aricept ), rivastigmine (Exelon ), lycoremine (Reminyl ), N-methyl-D-aspartate antagonist, for example U.S. dollar amine (Memantine) (Namenda ).Can give at least a cognitive raising medicine simultaneously with compound of the present invention, or give (with any order) in proper order with compound of the present invention.In addition, when in above-mentioned treatment, using, think this paper describe the combination can have add with or synergistic effect.
In another embodiment, the present invention relates to the method for prevention (formation) disease illness, for example, neurodegenerative disorders or neuropsychiatric illness.Term " prevention " the disease illness (through giving any compound described herein) that this paper uses; For example neurodegenerative disorders or neuropsychiatric illness; Be meant giving after this paper describes compound, do not form the detectable physiological characteristic or the symptom of disease or illness.Specifically, method of the present invention comprises: the described herein any compound or pharmaceutically acceptable salt thereof that needs patient (for example, Mammals, for example people) the treatment significant quantity of treatment.Perhaps, this method comprises: give the described herein any compound or pharmaceutically acceptable salt thereof of patient treatment significant quantity and at least a cognitive combination that improves medicine of treatment significant quantity.
In another embodiment, the present invention relates to the method for preventing disease illness development (for example, worsening), for example, neurodegenerative disorders or neuropsychiatric illness.This method comprises: the described herein any compound or pharmaceutically acceptable salt thereof that needs patient (for example, Mammals, for example people) the treatment significant quantity of treatment.Perhaps, this method comprises: give the described herein any compound or pharmaceutically acceptable salt thereof of patient treatment significant quantity and at least a cognitive combination that improves medicine of treatment significant quantity.
In the aforesaid method of formation that prevents neurodegenerative disorders or neuropsychiatry illness or development, the combination of one or more biomarker well known by persons skilled in the art, diagnostic test or biomarker and diagnostic test can be used for confirming: whether (1) patient is among the danger that forms one or more neurodegenerative disorders or neuropsychiatry illness; Or (2) formerly diagnose and suffer among the patient of one or more above-mentioned illness, and whether neurodegenerative disorders or neuropsychiatry illness develop (for example, worsening).
Another embodiment provides confirms that whether 11 beta-HSD 1 inhibitors need among its patient effective means in treatment.This method can be used for confirming the effect of 11 beta-HSD 1 inhibitors, comprises the unknown or confirms those suppressor factor with this effect.
The preparation of formula (I) compound
Abbreviation:Ac: ethanoyl; AcSH: thioacetic acid; Bu: butyl; Cbz: carbobenzoxy-(Cbz); CbzCl: Carbobenzoxy Chloride; DAST: (diethylamino) sulfur trifluoride DMSO: methyl-sulphoxide; DPPA: diphenyl phosphate azide; Et: ethyl; Et 3N: triethylamine; EtOH: ethanol; HPLC: performance liquid chromatography; LCMS: liquid chromatography/mass spectrometry; MCPBA: metachloroperbenzoic acid; Me: methyl; MeOH: methyl alcohol; Ms: methylsulfonyl; MsCl: methylsulfonyl chloride; NaOMe: sodium methylate; NaSMe: sodium methyl mercaptide; T-Bu: the tertiary butyl; T-BuOH: the trimethyl carbinol.
The method that is described below can be used various enantiomorphs.Can prepare compound of the present invention according to the compound method described in this part, method of the present invention and the embodiment part.Some group described in the reaction scheme just illustrates some substituting group that is included in the present invention, does not limit the meaning of the scope of the invention.Representational method is shown among (but being not limited to) reaction scheme 4-13.
Reaction scheme 4
Figure 563945DEST_PATH_IMAGE031
Of reaction scheme 4, formula (4-4) and compound (4-5) have wherein defined R in the present invention's general introduction 1, R 2, R 3, R 4, R 5And L, can be by the compound of formula (4-1).Correspondingly,, handle with HCl for example in the ethanol at solvent, the nitrile of formula (4-1) can change the imidoether of corresponding formula (4-2) into.The further example of preparation formula (4-2) compound can obtain in U.S. Patent application US2006/0025614.Then, can be in ethanol or phosphate buffered saline buffer handle the compound of formula (4-2), the compound of formula (4-3) is provided with cyanamide.Then, can be in the solvent of optionally heating, ethanol for example is with amine (R 1) (R 2) NH handles the compound of formula (4-3), obtains the compound of formula (4-4).Amine (R 1) (R 2) NH is commercially available, like the said preparation of following reaction scheme or like following said preparation: J. Med. Chem., 50,149-164 (2007); Bioorg. Med. Chem. Lett., 17,527-532 (2007); Bioorg. Med. Chem. Lett., 16,5555-5560 (2006); Bioorg. Med. Chem. Lett., 16,5414-5419 (2006); Bioorg. Med. Chem. Lett., 16,5408-5413 (2006); J. Am. Chem. Soc., 75,637-640 (1953); J. Med. Chem., 13,926-935 (1970); Australian J. Chem., 47,1833-1841 (1994); J. Org. Chem., 33,877-880 (1968).In similarly transforming, the compound of formula (4-2) can change the compound of formula (4-5) into.Formula (4-4) and compound (4-5) are the compounds of representational formula (I).
Reaction scheme 5
Figure 675120DEST_PATH_IMAGE032
Like 5 descriptions of reaction scheme, formula (4-4), (5-3) and compound (5-4), wherein R 1, R 2, R 3, R 4, R 5, R 6With L in the present invention general introduction definition, can be by the compound of formula (5-1).The compound of formula (5-1) can be like following said preparation: people such as Sorensen, Bioorg. Med. Chem. Lett.17,527-532 (2007).In addition, the preparation of formula (5-1) compound be described in following in: U.S. Pat 7,528,282; 7,511,175; 7,435,833 and 7,217,838; U. S. application discloses 2009/0054426,2008/0312214, and 2008/0076819,2006/0281773; 2005/0277747,2006/0149070,2007/0208001,2007/0129345; 2007/0167622,2007/0066584,2007/0088088; International Publication WO 2007118185, and WO 2007111921, and WO 2007145834, and WO 2007145835, and WO 2008088540, and WO 2008011453; WO 2008099145, and WO 2008012532, and WO 2008053194, and WO 2008024892, and WO 2008074384, and WO 2008052638; WO 2007124337, and WO 2007127765, and WO 2007127726, and WO 2007127693, and WO 2007127704, and WO 2007127688; WO 2007127901, and WO 2007127763, and WO 2007124329, and WO 2007124254, and WO 2007107470, and WO 2007101270; WO 2008069313, and WO 2007084314, and WO 2008157752, and WO 2008142859, and WO 2008006703; WO 2008006702, and WO 2007107550, and WO 2007115935, and WO 2007051810, and WO 2007051811; WO 2008110196, and WO 2007144394, and WO 2008134221, and WO 2008127924, and WO 2006048750; WO 2007058346, and WO 2007114124, and WO 2008142986, and WO 2007114125, and WO 2008101886; WO 2008101907, and WO 2008101885, and WO 2008101914, WO 2008119017 and U.S. Patent application US 11/697044, and this paper combines its full content with the mode of quoting as proof.When contact Lawesson's reagent in heated solvent (for example toluene), the compound of formula (5-1) can be converted into the thioamides of formula (5-2).Then, in the presence of mercuric acetate (II), choose wantonly in the presence of alkali (for example triethylamine), in the solvent (for example acetonitrile) of optionally heating, use formula H 2N-R 6, H 2N-CN or H 2N-OR 6Amine handle the compound of formula (5-2), formula (5-3), (4-4) and compound (5-4) are provided respectively.Formula (5-3), (4-4) and compound (5-4) are the compounds of representational formula (I).
Reaction scheme 6
Shown in reaction scheme 6, the compound of formula (6-5) has wherein defined R in the present invention's general introduction 1, R 2, R 3, R 4, R 5, L and W, can be by the compound of formula (6-1).The compound of formula (6-1), wherein LG is a leavings group, for example chlorine, bromine, iodine, trifluoromethanesulfonic acid base or tosic acid base can be in the presence of alkali (for example cesium carbonate), in the solvent of optionally heating (for example N, dinethylformamide), use H-L-R 5Handle, wherein L is O or S, obtains the compound of formula (6-2).Under condition known in the art, be hydrolyzed subsequently, the compound of formula (6-3) is provided.Use amido linkage formation condition known in the art, make the compound and the amine (R of formula (6-3) 1) (R 2) the NH coupling, obtain the compound of formula (6-4).Use reaction scheme 5 described methods, the compound of formula (6-4) changes the compound of formula (6-5) into.The compound of formula (6-5) is the compound of representational formula (I).
Reaction scheme 7
Figure 653758DEST_PATH_IMAGE034
Shown in reaction scheme 7, can be by compound (7-1) preparation compound (7-7).Can make compound (7-1) be converted into compound (7-2) with two steps.At first, in this case, show carbobenzoxy-(Cbz) with the amine protection.Utilize methods known in the art with the ester hydrolysis then.Like Tetrahedron Lett., 43,8687-8691 (2002) is said, handles compound (7-2), obtains compound (7-3).Can compound (7-3) hydrolysis be obtained compound (7-4) then.Then, with three the step can make compound (7-4) change into compound (7-5) ( Bioorg. Med. Chem. Lett., 17,527-532 (2002)).In the first step, with tertiary alcohol alkylsulfonylization.Then replace with thioacetic acid.The protection base is installed again, is obtained compound (7-5).Then, can remove the acetate groups of compound (7-5) with sodium methyl mercaptide.With the chloramines reaction, use the metachloroperbenzoic acid oxidation subsequently, obtain compound (7-6).Use methods known in the art, remove amine protecting group, obtain compound (7-7).Compound (7-7) is representational (R 1) (R 2) NH, and can in reaction scheme 4 and 6, use.
Reaction scheme 8
Figure 687573DEST_PATH_IMAGE035
Like 8 descriptions of reaction scheme, can be by compound (8-1) preparation compound (8-4).Of reaction scheme 7, when from compound (7-5), removing the acetate part, preparation compound (8-1).In the presence of alkali, can compound (8-1) be methylated with methyl-iodide, obtain compound (8-2).Can obtain sulfone (8-3) with sodium perborate with compound (8-1) oxidation.Use methods known in the art, remove amine protecting group, obtain compound (8-4).Compound (8-4) is representational (R 1) (R 2) NH, and can in reaction scheme 4 and 6, use.
Reaction scheme 9
As people such as Wilcox ( J. Org. Chem., 29,2209-2211 (1964)) said, can prepare compound (9-1).Utilize then people such as Wilcox ( J. Org. Chem., 33,877-880 (1968)) described method, compound (9-1) can change compound (9-2) into.Use ammonia treatment then, compound (9-2) can change compound (9-3) into.Perhaps, use reaction scheme 7 described methods, compound (9-2) can be converted into formula (9-4) and compound (9-6).Can also use the method in the reaction scheme 8, compound (9-2) changes compound (9-5) into.Compound (9-3), (9-4), (9-5) and (9-6) be representational (R 1) (R 2) NH, and can in reaction scheme 4 and 6, use.
Like 10 descriptions of reaction scheme, can come preparation formula (5-3), (4-4) and compound (5-4) by the compound of formula (5-2).At solvent (for example; Hot methylene dichloride) in; Can use triethyl oxygen
Figure 264365DEST_PATH_IMAGE037
a tetrafluoro borate to handle the compound of formula (5-2), obtain the compound of formula (10-1).Then can be of reaction scheme 5, the compound of processing formula (10-1) obtains formula (5-3), (4-4) and compound (5-4).Formula (5-3), (4-4) and compound (5-4) are the compounds of representational formula (I).
Reaction scheme 10
Reaction scheme 11
Figure 921403DEST_PATH_IMAGE039
Of reaction scheme 11, can be by the compound formula (11-2) and the compound (11-4) of formula (11-1).Compound (11-1), wherein v is 1 or 2, and R'' is an alkyl, and P is a nitrogen-protecting group, through removing said protection base, can change the compound of formula (11-2) into.Those skilled in the art can make employed protection base and protective reaction condition coupling.For example, when P is carbobenzoxy-(Cbz), in the presence of palladium catalyst, carry out hydrogenation, can remove P.
Can also the compound of (11-1) be reduced into the alcohol of corresponding formula (11-3).Use for example borine-THF mixture, can the ester moiety reduction of formula (11-1) compound be obtained the methylol in (11-3) compound.Can use the compound oxidation of reagent (the for example high iodine alkane of Dess-Martin), produce intermediate aldehydes formula (11-3).Use (diethylamino) sulfur trifluoride (DAST) to handle subsequently, change aldehyde into the difluoromethyl part.Under proper reaction conditions, remove the basic P of protection, the compound of formula (11-4) is provided.
Formula (11-2) and compound (11-4) are representational (R 1) (R 2) NH, and can in reaction scheme 4 and 6, use.
Reaction scheme 12
Shown in reaction scheme 12, the compound of formula (11-1) can also change formula (12-3) and compound (12-4) into.The compound of formula (11-2), wherein v is 1 or 2, and R'' is an alkyl, and P is a nitrogen-protecting group, through with the ester moiety hydrolysis, can change the compound of formula (12-1) into.Through handling with reagent (for example oxalyl chloride), the compound of formula (12-1) can change corresponding chloride of acid into.Can make midbody chloride of acid and ammonia react then, obtain the methane amide of formula (12-2).Under condition well known by persons skilled in the art, remove the protection base, the compound of formula (12-3) is provided.Can also use the compound dehydration of reagent (for example trifluoroacetic anhydride), partly change methane amide into cyanic acid formula (12-2).Remove the protection base, the compound of formula (12-4) is provided.Formula (12-2) and compound (12-4) are representational (R 1) (R 2) NH, and can in reaction scheme 4 and 6, use.
Reaction scheme 13
Figure 94076DEST_PATH_IMAGE042
Like 13 descriptions of reaction scheme, the compound of formula (13-1), wherein R'' is an alkyl, v is 1 or 2, can change the compound of formula (13-3) into.Correspondingly, can be under the Hunsdiecker reaction conditions compound of processing formula (13-1), change carboxylic moiety into corresponding bromide.Contact oxyhydroxide subsequently, bromizate thing and be converted into corresponding alcohol, and ester is hydrolyzed to the carboxylic acid of formula (13-2).In the presence of alcohol (the for example trimethyl carbinol), through handling with diphenyl phosphate azide, the Curtius that carries out formula (13-2) compound resets, and midbody carboxylamine tertiary butyl ester is provided.Through handling with acid (for example hydrochloric acid or trifluoroacetic acid), remove tertbutyloxycarbonyl, obtain the compound of formula (13-3).The compound of formula (13-3) is representational (R 1) (R 2) NH, and can in reaction scheme 4 and 6, use.
In addition, between the synthesis phase of formula (I) compound, can use nitrogen-protecting group to protect amino.This method is described among Greene and the Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999) with some suitable nitrogen-protecting groups.For example, suitable nitrogen-protecting group is including, but not limited to tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), benzyl (Bn), ethanoyl and trifluoroacetyl group.More particularly, through handling, can remove Boc protection base with acid (for example trifluoroacetic acid or hydrochloric acid).Can remove Cbz and Bn protection base through catalytic hydrogenation, it is basic with the trifluoroacetyl group protection to remove deacetylate through multiple condition (comprise and use sodium hydroxide, Pottasium Hydroxide or Lithium Hydroxide MonoHydrate, in moisture organic or alcoholic solvent).
Utilize the well-known method of organic synthesis those skilled in the art, can separate and purifying compound of the present invention and midbody.Separate with the example of the ordinary method of purifying compounds can including, but not limited to: compose recrystallization under high or low temperature (choose wantonly and use the activated carbon pre-treatment) in the enterprising circumstances in which people get things ready for a trip of solid carrier (for example, silica gel, aluminum oxide or with alkyl silane deutero-silicon-dioxide); Thin-layer chromatography, distillation under various pressure, vacuum-sublimation; Grind, for example, below described method: " Vogel's Textbook of Practical Organic Chemistry "; 5th edition (1989), people such as Furniss, pub. Longman Scientific & Technical; Essex CM20 2JE, England.
Some compounds of the present invention have at least one basic site, can use the s.t. compound thus, form needed salt.For example, can make compound and acid in room temperature or be higher than under the temperature of room temperature and react, needed salt is provided, make its deposition, after the cooling, filter and collect.The example of acid that is suitable for this reaction is including, but not limited to tartrate, lactic acid, succsinic acid, and racemic melic acid, atrolactic acid, methylsulfonic acid, ethyl sulfonic acid; Toluenesulphonic acids, naphthene sulfonic acid, carbonic acid, fumaric acid, glyconic acid, acetate, propionic acid; Whitfield's ointment, hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, Citric Acid or hydroxybutyric acid; Camphorsulfonic acid, oxysuccinic acid, toluylic acid, Aspartic Acid, L-glutamic acid, or the like.
The present invention includes pharmaceutically active compound, it can be formula (I) compound chemosynthesis or that pass through bio-transformation formation in the body.
With reference to the following example and reference implementation example, can understand compound of the present invention, compsn and method better, it only is used to illustrate, and does not limit the scope of the invention.
Embodiment
The preparation of Wyovin
Wyovin midbody 1 (BAI-1)
1-(2-chloroethyl) hexanaphthene-1,4-dioctyl phthalate dimethyl esters
In nitrogen atmosphere, freshly prepd lithium diisopropylamine (Diisopropylamine of the n-Butyl Lithium of 110.0 mL (2.5 M solution are in hexane) and 41.0 mL-30 ℃, in 300 mL THFs, mix) is cooled to-78 ℃, and stirred 30 minutes.With dropwise adding anhydrous hexamethylphosphoramide (180 mL, 1.0 mol) in 30 minutes.Add hexanaphthene-1,4-dioctyl phthalate dimethyl esters (50 g, 0.25 mol) in the mixture that obtains with 30 fens clockwise.After stirring 1 hour, with 1 hour adding 1-bromo-2-monochloroethane (21 mL, 0.25 mol).Down stirred these mixtures 3 hours at-78 ℃ then, stirred overnight then, and be warming up to room temperature.In this reaction mixture, add HCl (3N, 100 mL), and mixture was stirred 10 minutes.Come except that desolvating through reduction vaporization.Water layer is extracted with ETHYLE ACETATE (3 * 150 mL).With the extract that merges with HCl (3 N, 2 * 100 mL), water (200 mL), saturated NaHCO 3Na is used in the aqueous solution (100 mL), salt solution (2 * 100 mL) washing 2SO 4Dry.Concentrate, obtain title compound, it just need not be further purified and can in next step, use.
The preparation of Wyovin midbody 2 (BAI-2)
Two ring [2.2.2] octanes-1,4-dioctyl phthalate dimethyl esters
In nitrogen atmosphere, freshly prepd lithium diisopropylamine (Diisopropylamine of the n-Butyl Lithium of 110.0 mL (2.5 M solution are in hexane) and 41.0 mL-30 ℃, in 150 mL THFs, mix) is cooled to-78 ℃, and stirred 30 minutes.Under-78 ℃, in nitrogen atmosphere, with 1-(2-chloroethyl) hexanaphthene-1,4-dioctyl phthalate dimethyl esters (BAI-1,70 g, 0.25 mol) and anhydrous hexamethylphosphoramide (180 mL, the 1.0 mol) mixture in THF (500 mL) stirred 30 minutes.Through transfer line, with the 1 hour above-mentioned lithium diisopropylamine solution of adding in this solution.Under-78 ℃, the mixture that obtains was stirred 2 hours, then be heated to room temperature.At room temperature after the stirred overnight, add saturated NH 4The Cl aqueous solution.This mixture is concentrated into 1/2 volume, extracts then with the dilution of 500 mL water, and with hexane (3 * 300 mL).The extract that merges is used brine wash, use dried over sodium sulfate, concentrate.With the bullion crystallization, obtain title compound with hexane. 1H?NMR(400?MHz,?CDCl 3),?δ?ppm?3.65(s,?6H),?1.81(s,?12H);?LCMS(ESI+)?m/ z227(M+H) +。
The preparation of Wyovin midbody 3 (BAI-3)
Two ring [2.2.1] heptane-1,4-dioctyl phthalate dimethyl esters
In nitrogen atmosphere, freshly prepd lithium diisopropylamine (Diisopropylamine of the n-Butyl Lithium of 15 mL (2.5 M solution are in hexane) and 5 mL-30 ℃, in 50 mL THFs, mix) is cooled to-78 ℃, and stirred 30 minutes.With 10 fens clockwise pentamethylene-1, new lithium diisopropylamine solution (75 ℃～-70 ℃) above being added dropwise in THF (12 mL) solution of 3-dioctyl phthalate dimethyl esters (2.67 g, 14.37 mmol).Remove cryostat then, and this mixture is warming up to 0 ℃, and under this temperature, kept 20 minutes, then be cooled to-80 ℃.Join (75 ℃～-70 ℃) in this reaction mixture at leisure with 35 minutes THF (25 mL) solution with bromochloroethane (2 mL, 24 mmol).With this reaction soln stirred overnight, little by little be warming up to room temperature simultaneously then.Through adding saturated NH 4Cl solution (20 mL) comes this reaction of quencher.Except that after desolvating, add 200 mL ETHYLE ACETATE.With 2N HCl (120 mL * 2) washing organic phase, use brine wash, then use Na 2SO 4Dry.After filtering and concentrating,, obtain title compound through silica gel chromatography resistates (with ethyl acetate/petroleum ether=1/10 wash-out). 1H?NMR(400?MHz,?CDCl 3),?δ(ppm):?3.68(s,?6H),?2.02~2.03(m,?4H),?1.91(s,?2H),?1.68(s,?4H);?LCMS(ESI+)?m/z?213.1(M+H) +。
The preparation of Wyovin midbody 4 (BAI-4)
4-(methoxycarbonyl) two ring [2.2.2] octane-1-formic acid
With two ring [2.2.2] octanes-1, methyl alcohol (500 mL) solution of 4-dioctyl phthalate dimethyl esters (BAI-2,22 g, 0.1 mol) is heated to gentle reflux.With methyl alcohol (100 mL) that adds KOH (5.6 g, 0.1 mol) in 30 fens this solution of clockwise and water (10 mL) solution.Then with this reaction mixture refluxed 24 hours.Be cooled to after the room temperature, remove and desolvate, and dilute with water.Extract the aqueous solution with ETHYLE ACETATE (100 mL * 2), remove starting raw material BAI-2, then water layer is acidified to pH～3 through adding dense HCl.Form deposition, and extract with ETHYLE ACETATE (250 mL * 3).With the extract that brine wash merges, use Na 2SO 4Drying, evaporation obtains title compound. 1H?NMR(400?MHz,?DMSO- d 6)δ?ppm?12.09(s?1H),?3.57(s,?3H),?1.70(s,?12H);?LCMS(ESI+)?m/ z213(M+H) +。
The preparation of Wyovin midbody 5 (BAI-5)
4-(methoxycarbonyl) two ring [2.2.1] heptane-1-formic acid
Method described in the preparation of use BAI-4, by two ring [2.2.1] heptane-1,4-dioctyl phthalate dimethyl esters (BAI-3) preparation title compound. 1H?NMR(400?MHz,?DMSO- d 6),?δ?ppm?11.99(br,?1H),?3.60(s,?3H),?1.90~1.92(m,?4H),?1.76(s?2H),?1.57~1.60(m,?4H);?LCMS(ESI+)?m/ z199.1(M+H) +。
The preparation of Wyovin midbody 6 (BAI-6)
4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.2] octane-1-methyl-formiates
In the mixture of two ring [2.2.2] octane-1-formic acid (BAI-4,11.0 g, 0.05 mol) of the 4-(methoxycarbonyl) in toluene (200 mL), triethylamine (7.5 g, 0.075 mol), add diphenyl phosphate azide (16.5 g, 0.06 mol).After the refluxing and stirring 2 hours, add phenylcarbinol (8.1 g, 0.075 mol), and this mixture backflow is spent the night.Except that after desolvating, resistates is dissolved in the ETHYLE ACETATE, and uses saturated NaHCO 3Solution washing.After concentrating,, obtain title compound with anti-phase purification by flash chromatography resistates (30-60% methyl alcohol is in water). 1H?NMR(400?MHz,?CDCl 3),?δ?ppm?7.27~7.37(m,?5H),?5.02(s,?2H),?4.68(s,?1H),?3.63(s,?3H),?1.87(s,?12H);?LCMS(ESI+)?m/ z318(M+H) +。
The preparation of Wyovin midbody 7 (BAI-7)
4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.1] heptane-1-methyl-formiates
Use the employed method of preparation BAI-6, by 4-(methoxycarbonyl) two ring [2.2.1] heptane-1-formic acid (BAI-5) preparation title compound.LCMS(ESI+)?m/ z304.1(M+H) +。
The preparation of Wyovin midbody 8 (BAI-8)
4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.2] octane-1-formic acid
To 4-{ [(benzyloxy) carbonyl] amino } add the NaOH aqueous solution (50 mL, 0.1 mol) in methyl alcohol (200 mL) solution of two ring [2.2.2] octane-1-methyl-formiates (BAI-6,10.3 g, 32.5 mmol).With this reaction mixture refluxed 2 hours.Except that after desolvating, extract resistates with ETHYLE ACETATE (50 mL * 2).With dense HCl water layer is adjusted to pH=2, and extracts with ETHYLE ACETATE (200 mL * 4).With the extract that brine wash merges, use dried over sodium sulfate, concentrate, obtain title compound. 1H?NMR(400?MHz,?CDCl 3),?δ?ppm?7.33~7.36(m,?5H),?5.03(s,?2H),?4.61(s,?1H), 1.89(s,?12H);?LCMS(ESI+)?m/ z304(M+H) +。
The preparation of Wyovin midbody 9 (BAI-9)
4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.1] heptane-1-formic acid
Use the employed method of preparation BAI-8, by 4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.1] heptane-1-methyl-formiate (BAI-7) preparation title compound. 1H?NMR(400?MHz,?DMSO- d 6),?δ?ppm?12.14(br,?1H),?7.57(br,?1H),?7.31~7.37(m,?5H),?4.99(s,?2H),?1.83~1.93(m,?4H),?1.79(s,?2H),?1.55~1.64(m,?4H);?LCMS(ESI+)?m/ z290.1(M+H) +。
The preparation of Wyovin midbody 10 (BAI-10)
(4-formamyl two ring [2.2.2] suffering-1-yls) carboxylamine benzyl ester
Under nitrogen atmosphere, to ice-water bath refrigerative 4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.2] octane-1-formic acid (BAI-8,3.03 g, anhydrous CH 0.01mol) 2Cl 2Add oxalyl chloride (1.9 g, 0.015 mol) in (80 mL) solution.At room temperature stirred this mixture 1 hour.Removal of solvent under reduced pressure and excessive oxalyl chloride.The resistates that obtains is dissolved in anhydrous CH 2Cl 2In (50 mL), and with NH 3Gas blasts with in this solution of ice bath refrigerative.At room temperature the mixture that obtains was stirred 5 minutes, and use CH 2Cl 2Dilution.Water, this solution of brine wash are used dried over sodium sulfate.Concentrate, obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.31~7.36(m,?5H),?5.51(br,?2H),?5.03(s,?2H),?4.63(s,?1H), 1.89(s,?12H);?LCMS(ESI+)?m/ z303(M+H) +。
The preparation of Wyovin midbody 11 (BAI-11)
(4-formamyl two ring [2.2.1] heptan-1-yl) carboxylamine benzyl ester
Employed method in the preparation of use BAI-10 is by 4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.1] heptane-1-formic acid (BAI-9) preparation title compound. 1H?NMR(400?MHz,?CDCl 3),?δ?ppm?7.30~7.36(m,?5H),?5.74(br,?1H),?5.59(br,?1H),?5.07(s,?2H),?1.99~2.02(m,?6H),?1.75~1.77(m,?4H);?LCMS(ESI+)?m/ z?289.1(M+H) +。
The preparation of Wyovin midbody 12 (BAI-12)
(4-cyano-bicyclo [2.2.2] suffering-1-yl) carboxylamine benzyl ester
At 0 ℃, to (4-formamyl two ring [2.2.2] suffering-1-yls) carboxylamine benzyl ester (BAI-10,3.0g, anhydrous CH 0.01mol) 2Cl 2(50 mL) solution and triethylamine (3.03g, 0.03mol) the middle trifluoroacetic anhydride (3.15 g, 0.015 mol) that adds.Add after the completion, this solution is warming up to room temperature, and continue stirred overnight.Use CH 2Cl 2After (100 mL) dilution, use saturated NaHCO 3The aqueous solution (50 mL * 3), water, this solution of brine wash, and use dried over sodium sulfate.Evaporation obtains title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.33~7.36(m,?5H),?5.02(s,?2H),?4.60(s,?1H), 2.01~2.05(m,?6H),?1.88~1.92(m,?6H);?LCMS(ESI+)?m/ z285(M+H) +。
The preparation of Wyovin 1 (BA-1)
4-amino bicyclic [2.2.2] octane-1-nitrile
In methyl alcohol (100 mL) solution of (4-cyano-bicyclo [2.2.2] suffering-1-yl) carboxylamine benzyl ester (BAI-12,2.1 g, 7.4 mmol), add Pd (OH) 2/ C (100 mg).At room temperature blasted hydrogen 1 hour to this stirred reaction mixture.After the filtration, concentrated filtrate obtains title compound. 1H?NMR(400?MHz,?DMSO- d 6)δ?ppm?8.08(s,?2H),?1.98~2.02(m,?6H),?1.70~1.74(m,?6H);?LCMS(ESI+)?m/ z151(M+H) +。
The preparation of Wyovin 2 (BA-2)
4-amino bicyclic [2.2.2] octane-1-methyl-formiate
To 4-{ [(benzyloxy) carbonyl] amino } two the ring [2.2.2] octane-1-methyl-formiates (BAI-6,951 mg, 3 mmol) methyl alcohol (50 mL) solution in add Pd (OH) 2/C (100 mg).At room temperature blasted hydrogen 1 hour to this stirred reaction mixture.After the filtration, concentrated filtrate obtains title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?3.64(s,?3H),?1.84~1.88(m,?6H),?1.73(s,?2H),?1.53~1.57(m,?6H);?LCMS(ESI+)?m/ z184(M+H) +。
The preparation of Wyovin 3 (BA-3)
4-amino bicyclic [2.2.1] heptane-1-methyl-formiate
Use the described method of preparation BA-2, by 4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.1] heptane-1-methyl-formiate (BAI-7) preparation title compound.LCMS(ESI+)?m/ z170.1(M+H) +。
The preparation of Wyovin midbody 13 (BAI-13)
[4-(methylol) two ring [2.2.2] suffering-1-yls] carboxylamine benzyl ester
To with ice bath refrigerative 4-{ [(benzyloxy) carbonyl] amino } (BAI-8,1.0 g dropwise add borine/tetrahydrofuran solution (1M, 1 mL) to two ring [2.2.2] octane-1-formic acid in anhydrous tetrahydro furan 3.3mmol) (10 mL) solution.Releasing hydrogen gas, and the settled solution that obtains at room temperature stirred 1 hour.The water cancellation should be reacted, and used K 2CO 3The aqueous solution is handled water, and extracts with ETHYLE ACETATE (50 mL * 3).With the organic phase that brine wash merges, use dried over sodium sulfate, concentrate, obtain title compound.LCMS(ESI+)?m/ z290(M+H) +。
The preparation of Wyovin midbody 14 (BAI-14)
[4-(methylol) two ring [2.2.1] heptan-1-yl] carboxylamine benzyl ester
Method described in the preparation of use BAI-13 is by 4-{ [(benzyloxy) carbonyl] amino } two ring [2.2.1] heptane-1-methyl-formiates (BAI-7) preparation title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.31~7.36(m,?5H),?5.06(s,?2H),?3.64(s,?2H),?1.92~1.93(m,?2H),?1.67~1.78(m,?4H),?1.43(s,?2H),?1.38~1.41(m,?2H);?LCMS(ESI+)?m/ z275.1(M+H) +。
The preparation of Wyovin midbody 15 (BAI-15)
(4-formyl radical two ring [2.2.2] suffering-1-yls) carboxylamine benzyl ester
Anhydrous CH to [4-(methylol) two ring [2.2.2] suffering-1-yls] carboxylamine benzyl ester (BAI-13,1.00 g, 3.5 mmol) 2Cl 2Add the high iodine alkane of Dess-Martin (1.7 g, 4.0 mmol) in (25 mL) solution in batches.It is muddy that settled solution becomes, and stirred 2 hours.Use CH 2Cl 2(100 mL) dilutes this reaction mixture, then adds the NaOH aqueous solution (1 N, 10 equivalents).The suspension-s that obtains was stirred 30 minutes.Use CH 2Cl 2Extract water layer, and with the organic phase that merges with the 1N NaOH aqueous solution, water, brine wash, use dried over sodium sulfate.Concentrate, obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?9.44(s,?1H)7.31~7.37(m,?5H),?5.03(s,?2H),?4.66(s,?1H),?1.88~1.92(m,?6H),?1.71~1.75(m,?6H);?LCMS(ESI+)?m/ z288(M+H) +。
The preparation of Wyovin midbody 16 (BAI-16)
(4-formyl radical two ring [2.2.1] heptan-1-yl) carboxylamine benzyl ester
Use the employed method of preparation BAI-15, prepare title compound by [4-(methylol) two rings [2.2.1] heptan-1-yl] carboxylamine benzyl ester (BAI-14).LCMS(ESI+)?m/ z274.1(M+H) +。
The preparation of Wyovin midbody 17 (BAI-17)
[4-(difluoromethyl) two ring [2.2.2] suffering-1-yls] carboxylamine benzyl ester
Anhydrous CH to (4-formyl radical two ring [2.2.2] suffering-1-yls) carboxylamine benzyl ester (BAI-15,920 mg, 3.2 mmol) 2Cl 2Add (diethylamino) sulfur trifluoride (516 mg, 3.2 mmol) in (10 mL) solution.At room temperature stirred this reaction mixture 2 hours, and pour in the water (10 mL).The mixture that obtains was stirred 30 minutes.Separate organic layer, and use saturated NaHCO 3The aqueous solution, water and brine wash are used dried over sodium sulfate.Concentrate, obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.32~7.35(m,?5H),?5.36(t, J=56.8Hz,?1H)5.03(s,?2H),?4.60(s,?1H),?1.85~1.89(m,?6H),?1.62~1.66(m,?6H);?LCMS(ESI+)?m/ z310(M+H) +。
The preparation of Wyovin midbody 18 (BAI-18)
[4-(difluoromethyl) two ring [2.2.1] heptan-1-yl] carboxylamine benzyl ester
Use the method described in the preparation of BAI-17, prepare title compound by (4-formyl radical two rings [2.2.1] heptan-1-yl) carboxylamine benzyl ester (BAI-16). 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.33~7.36(m,?5H),?5.78(t, J=56.7Hz,?1H),?5.07(s,?2H),?1.83~1.96(m,?5H),?1.73~1.77(m,?5H);?LCMS(ESI+)?m/ z296.1(M+H) +。
The preparation of Wyovin 4 (BA-4)
4-(difluoromethyl) two ring [2.2.2] suffering-1-amine
In methyl alcohol (100 mL) solution of [4-(difluoromethyl) two ring [2.2.2] suffering-1-yls] carboxylamine benzyl ester (BAI-17,600 mg, 2 mmol), add Pd (OH) 2/ C (100 mg).At room temperature blasted hydrogen 0.5 hour to this stirred reaction mixture.After the filtration, concentrated filtrate obtains title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?5.37(t, J=56.8Hz,?1H),?1.60~1.64(m,?6H),?1.52-1.56(m,?6H),?1.45(s,?2H)。
The preparation of Wyovin 5 (BA-5)
4-(difluoromethyl) two ring [2.2.1] heptan-1-amine
Use the method described in the preparation of BA-4, prepare title compound by [4-(difluoromethyl) two rings [2.2.1] heptan-1-yl] carboxylamine benzyl ester (BAI-18). 1H?NMR(400?MHz,?CDCl 3)δ?ppm?5.76(t, J=56.7Hz,?1H),?2.01(s,?2H,?1.81~1.88(m,?2H),?1.61~1.65(m,?4H),?1.48~1.55(m,?2H),?1.44(s,?2H);?LCMS(ESI+)?m/ z162.1(M+H) +。
The preparation of Wyovin 6 (BA-6)
4-amino bicyclic [2.2.2] octane-1-methane amide
In methyl alcohol (100 mL) solution of (4-formamyl two ring [2.2.2] suffering-1-yls) carboxylamine benzyl ester (BAI-10,780 mg, 2.58 mmol), add Pd (OH) 2/ C (100 mg).At room temperature in this stirred reaction mixture, blasted hydrogen 2 hours.After the filtration, concentrated filtrate obtains title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?5.57(br,?2H),?1.84~1.88(m,?6H),?1.53~1.59(m,?6H)。
The preparation of Wyovin 7 (BA-7)
4-amino bicyclic [2.2.1] heptane-1-methane amide
Use the method described in the preparation of BA-6, prepare title compound by (4-formamyl two rings [2.2.1] heptan-1-yl) carboxylamine benzyl ester (BAI-11). 1H?NMR(400?MHz,?DMSO- d 6)δ?ppm?6.96(s,?1H),?6.74(s,?1H),?1.76~1.83(m,?2H),?1.50~1.55(m,?4H),?1.44(s,?2H),?1.40~1.42(m,?2H);?LCMS(ESI+)?m/ z 155.1(M+H) +。
The preparation of Wyovin midbody 19 (BAI-19)
4-bromine two ring [2.2.2] octane-1-methyl-formiates
In acetone (3 mL) suspension-s of 4-(methoxycarbonyl) two ring [2.2.2] octane-1-formic acid (BAI-4,0.424 mg, 2 mmol), add phenolphthalein.In this mixture, add the 1M NaOH aqueous solution (about 2 mL, 1 equivalent), till the color of this solution becomes redness.Then, add AgNO 3(340 mg, the 2 mmol) aqueous solution (0.5 mL).Filter and collect the deposition that forms, water, acetone and diethyl ether washing were 100 ℃ of following vacuum-dryings 6 hours.The solid suspension that obtains in hexane (5 mL), is at room temperature dropwise joined bromine (260 mg, 1.62 mmol) in this reaction mixture then.Add after the completion, this reaction mixture was at room temperature stirred 30 minutes.Filter this reaction mixture, remove solid, and filter cake is washed with hexane (100 mL).Use saturated NaHCO 3Organic filtrating that washing merges is used MgSO 4Drying is filtered, and concentrates, and obtains title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?3.64(s,?3H),?2.18~2.27(m,?6H),?1.94~1.98(m,?6H);?GCMS m/z248(M+H) +。
The preparation of Wyovin midbody 20 (BAI-20)
4-hydroxyl two ring [2.2.2] octane-1-formic acid
4-bromine two ring [2.2.2] octane-1-methyl-formiates (BAI-19,0.246 g, 0.001 mol) were refluxed 24 hours in 25 mL, 1% sodium hydroxide solution.After the cooling,, and extract with ether (50 mL * 6) with this reaction soln of 6N hcl acidifying.The ether layer that merges is used dried over mgso, and be concentrated into little volume.With normal hexane and diethyl ether (40:10 mL) recrystallization, obtain title compound. 1H?NMR(400?MHz,?DMSO- d 6)δ?ppm?1.1.68-1.78(m,?6H),?1.48-1.52(m,?6H),?4.00(s,?1H),?12.00(s,?1H)。
The preparation of Wyovin midbody 21 (BAI-21)
(4-hydroxyl two ring [2.2.2] suffering-1-yls) carboxylamine tertiary butyl ester
To 4-hydroxyl two ring [2.2.2] octane-1-formic acid (BAI-20; 340 mg; 2 mol) two
Figure 403834DEST_PATH_IMAGE007
add triethylamine (202 mg in alkane (5 mL) solution; 2 mmol), the diphenyl phosphate azide (550 mg, 2 mmol) and the trimethyl carbinol (3 g, 40 mmol).Stirred this reaction mixture 45 minutes, 80 ℃ of stirred overnight.This mixture of concentrating under reduced pressure then.Resistates is dissolved in the 30 mL ETHYLE ACETATE, then uses saturated NaHCO 3And brine wash.Use anhydrous Na 2SO 4Dry organic layer concentrates, and obtains the bullion title compound, and it just need not be further purified can be used for next step.
The preparation of Wyovin 8 (BA-8)
4-amino bicyclic [2.2.2] suffering-1-alcohol
CH to (4-hydroxyl two ring [2.2.2] suffering-1-yls) carboxylamine tertiary butyl ester (BAI-21,241 mg, 1 mmol) 2Cl 2Add 1.14 g trifluoroacetic acids (10 mmol) in (5 mL) solution.With this mixture stirred overnight at room temperature.Removal of solvent under reduced pressure obtains the trifluoroacetate of title compound.LCMS(ESI+)?m/ z142(M+H) +。
The preparation of N-cyanic acid-2-methyl-2-phenoxy third imido acid ethyl ester (CI-1)
Steps A
2-methyl-2-phenoxy propionic acid ethyl ester
In the mixture of phenol in acetonitrile (0.01 mol) and 2 bromo 2 methyl propionic acid ethyl ester (0.01 mol), add Cs 2CO 3(0.015mol), and with this reaction mixture refluxed spend the night.Except that after desolvating, resistates is distributed between ETHYLE ACETATE and water.With the 1N NaOH aqueous solution, water and brine wash organic layer, then use dried over sodium sulfate.Concentrate, obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.21~7.25(m,?2H),?6.98(t, J=7.2Hz?1H),?6.83~6.86(m,?2H),?4.23(q, J=7.2Hz?4H),?1.60(s,?6H),?1.24(t, J=7.2Hz?3H);?LCMS(ESI+)?m/ z209(M+H) +。
Step B
2-methyl-2-phenoxy propionic acid
The adding LiOH aqueous solution in methyl alcohol (200 mL) solution of the 2-of steps A methyl-2-phenoxy propionic acid (0.05 mmol) (150 mL, 1mol).With this reaction mixture refluxed 3 hours.Except that after desolvating, extract resistates with ETHYLE ACETATE (50 mL * 2).With dense HCl water layer is adjusted to pH=2, and extracts with ETHYLE ACETATE (200 mL * 4).With the extract that brine wash merges, use dried over sodium sulfate, concentrate, obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.26~7.30(m,?2H),?7.06(t, J=7.2Hz?1H),?6.93~6.95(m,?2H),?1.61(s,?6H);?LCMS(ESI+)?m/ z181(M+H) +。
Step C
2-methyl-2-phenoxy propionic acid amide
Under nitrogen atmosphere, to anhydrous CH with 2-methyl-2-phenoxy propionic acid (0.01 mol) of ice-water bath refrigerative step B 2Cl 2Add oxalyl chloride (1.9 g, 0.015 mol) in (150 mL) solution.At room temperature stirred this mixture 1 hour.Removal of solvent under reduced pressure and excessive oxalyl chloride.The resistates that obtains is dissolved in anhydrous CH 2Cl 2In (50 mL), and with NH 3Gas blasts with in this solution of ice bath refrigerative.At room temperature the mixture that obtains was stirred 5 minutes, and use CH 2Cl 2Dilution.Water and brine wash organic phase are used dried over sodium sulfate, concentrate, and obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.27~7.31(m,?2H),?7.08(t, J=7.6Hz?1H),?6.95~6.97(m,?2H),?5.98(s,?1H),?1.61(s,?6H);?LCMS(ESI+)?m/ z180(M+H) +。
Step D
2-methyl-2-phenoxypropionitrile
At 0 ℃, to the anhydrous CH of the 2-of step C methyl-2-phenoxy propionic acid amide (0.01 mol) 2Cl 2Add trifluoroacetic anhydride (3.1 5 g, 0.015 mol) in (50 mL) and triethylamine (3.03 g, the 0.03 mol) solution.Add after the completion, this solution is warming up to room temperature, and continues stirred overnight at ambient temperature.Then with this reaction mixture refluxed 3 hours.After being cooled to room temperature, use CH 2Cl 2(100 mL) dilution, this solution is used saturated NaHCO 3The aqueous solution (50 ml * 3), water and brine wash are used dried over sodium sulfate.Evaporation obtains title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.32~7.36(m,?2H),?7.14~7.20(m,?3H),?1.71(s,?6H)。
Step e
N-cyanic acid-2-methyl-2-phenoxy third imido acid the ethyl ester
2-methyl-2-the phenoxypropionitrile (0.05 mol) that in the ethanolic soln of sodium (0.02 mol) and the freshly prepd sodium ethylate of ethanol (50 mL), adds step D.At room temperature stir this mixture overnight, then add acetate (0.07 mol), then add NH 2CN (0.05 mol).Stirred this mixture 3 hours, and solvent is removed.With silica gel chromatography resistates (mobile phase: petrol ether/ethyl acetate=4:1～1:1), obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.27(t, J=8.0Hz?2H),?7.05(t, J=7.2Hz?1H),?6.88~6.90(m,?2H),?4.38(q, J=7.2Hz,?2H),?1.61(s,?6H),?1.39(t, J=7.2Hz,?3H);?LCMS(ESI+)?m/ z233(M+H) +。
Embodiment 1
(1E)-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl-prop amidine
A-958549 embodiment 1A
(1E)-2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-hydroxyl-2-adamantyl]-the 2-methyl propanamide
According to people such as Sorensen ( Bioorg. Med. Chem. Lett.2007,17,527-532) described method, synthesising title compound.
Embodiment 1B
(1E)-2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl thiopropionamide
In toluene (25 mL) solution of embodiment 1A (0.76 g, 2 mmol), add Lawesson's reagent (0.81 g, 2 mmol), then heated this reaction mixture 4 hours down at 80 ℃.With this reaction mixture concentrating under reduced pressure, and with resistates at saturated NaHCO 3Distribute between the aqueous solution and the ETHYLE ACETATE.Organic layer is merged dry (MgSO 4), filter, concentrate.With purification by flash chromatography resistates (SiO 2, the 0-40% ethyl acetate/hexane), title compound is provided.MS(DCI +)?m/ z398(M+H) +。
Embodiment 1C
(1E)-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl-prop amidine
With embodiment 1B (0.46 g; 2.0 acetonitrile mmol) (20 mL) solution is with cyanamide (0.12 g, 2.9 mmol), mercuric acetate (II) (0.56 g, 1.7 mmol) and triethylamine (0.33 mL; 2.3 mmol) handle, and reaction mixture heated 18 hours down at 80 ℃.Then with this mixture concentrating under reduced pressure, and with resistates at saturated NaHCO 3And distribute between the ETHYLE ACETATE.With the dry (MgSO of the organic layer that merges 4), filter, concentrate, and (hexane-ETHYLE ACETATE 1:2), obtains title compound with purification by flash chromatography with resistates. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.36-1.81(m,?16?H),?1.97-2.09(m,?1?H),?2.15-2.28(m,?2?H),?4.01(s,?1?H),?4.51(s,?1?H),?7.16-7.35(m,?2?H),?7.57(dd, J=8.5,?3.1?Hz,?1?H),?7.88(d, J=7.1?Hz,?1?H);?MS(DCI +)?m/ z406(M+H) +。
Embodiment 2
(1E)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-(2-aminomethyl phenyl) ethanamidine
With E-2-amino-5-hydroxyadamantane (people such as Jaroskova; Tetrahedron Letters 2006; 47 (46), 8063-8067) (0.35 g, 2.0 mmol) and (E)-N-cyanic acid-2-o-tolyl imido is by ETHYLE ACETATE (acetimidate; The open US2006/0025614 of U.S. Patent application) mixture of (0.42 g, 2.0 mmol) is in ethanol (1 mL), 80 ℃ of following stirrings 16 hours.On rotatory evaporator, concentrate this reaction mixture, and use purification by flash chromatography, use the 0-100% ethyl acetate/hexane, title compound is provided as elutriant. 1H NMR (300 MHz, DMSO -d 6) δ ppm 1.38 (d, J=12.9 Hz, 2 H), 1.55-1.90 (m, 7 H), 1.93-2.20 (m, 4 H), 2.30 (s, 3 H), 3.89 (s, 2 H), 3.95 (dd, J=6.3,3.2 Hz, 1 H), 4.43-4.52 (m, 1 H), 7.00 (dd, J=5.1,3.7 Hz, 1 H), 7.12-7.32 (m, 3 H), 8.57 (d, J=6.8 Hz, 1 H ); MS (DCI +) m/ z324 (M+H) +. C 21H 27ClN 2O 3S 20.5H 2The analytical calculation value of O: C, 72.26; H, 7.88; N, 12.64. measured value: C, 72.82; H, 7.65, N, 13.08.
Embodiment 3
1-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] the tetramethylene carbonamidine
Embodiment 3A
1-(4-chloro-phenyl-) tetramethylene first imido acid (carbimidate) carbethoxy hydrochloride
Under 0 ℃, (5.0 g, 26.1 mmol Aldrich) and in ethanol (2.3 mL, the 39.1 mmol) solution blasted HCl gas 30 minutes to refrigerative 1-(4-chloro-phenyl-) cyclobutyronitrile.After under 4 ℃, leaving standstill 24 hours, concentrate this reaction mixture, and grind with diethyl ether.Collecting precipitation, drying obtains title compound.MS(ESI +)?m/ z238(M+H) +。
Embodiment 3B
1-(4-chloro-phenyl-)-N-cyanocyclobutane first imido acid ethyl ester
To embodiment 3A (2.5 g; 9.1 add monosodium phosphate monohydrate (5.0 g in acetonitrile mmol) (7 mL) solution; 36.5 mmol), the aqueous solution (70.0 mL) of sodium phosphate dibasic heptahydrate (4.9 g, 18.2 mmol) and cyanamide (0.8 g, 18.2 mmol).At room temperature stir this reaction mixture 72 hours, and then used methylene dichloride (3 * 30 mL) to extract this mixture.Use anhydrous Na 2SO 4The dry organic extraction that merges filters, and concentrating under reduced pressure obtains title compound.MS(ESI +)?m/ z263(M+H) +。
Embodiment 3C
1-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] the tetramethylene carbonamidine
With E-2-amino-5-hydroxyadamantane (people such as Jaroskova, Tetrahedron Letters 2006,47 (46), 8063-8067) mixture of (0.2 g, 1.2 mmol) and embodiment 3B (0.3 g, 1.2 mmol) stirred 16 hours down at 80 ℃.Cool off this reaction mixture then, be dissolved in the methylene dichloride (2 mL), use purified, use Analogix Intelliflash 280 TM(SiO 2, the 0-100% ethyl acetate/dichloromethane), obtain title compound. 1H NMR (300 MHz, DMSO -d 6) δ ppm 1.29-1.46 (m, 2 H), 1.52-1.69 (m, 6 H), 1.71-1.82 (m, 2 H); (1.82-1.95 m, 2 H), 1.99-2.08 (m, 1 H), 2.11-2.24 (m, 2 H); (2.60-2.73 m, 2 H), 2.72-2.87 (m, 2 H), 3.62-3.89 (m; 1 H), 4.44 (s, 1 H), 7.48 (d J=8.3 Hz, 2 H), 7.66 (d, J=5.6 Hz, 1 H), 7.70 (d, J=8.7 Hz, 2 H)); MS (ESI +) m/ z384 (M+H) +. C 22H 26ClN 3The analytical calculation value of O: C, 68.83; H, 6.83; N, 10.95. measured value: C, 69.05; H, 7.28; N, 10.46.
Embodiment 4
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene base)-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine
Embodiment 4A
2-(2,4 difluorobenzene base) imido is by ethyl acetate hydrochloride
Use the described method of embodiment 3A, handle 2-(2,4 difluorobenzene base) acetonitrile (Aldrich), HCl gas and the ethanol that are purchased, only the reaction times is 72 hours, obtains title compound.MS(ESI +)?m/ z200(M+H) +。
Embodiment 4B
N-cyanic acid-2-(2,4 difluorobenzene base) imido is by ETHYLE ACETATE
Diethyl ether (25 mL) solution that in ethanol (100 mL) solution of embodiment 4A (7.0 g, 29.7 mmol), adds cyanamide (1.25 g, 29.7 mmol).At room temperature stirred this reaction mixture 3 days.Filter this reaction mixture then, and it is concentrated to filtrate, and obtains title compound.MS(ESI +)?m/ z225(M+H) +。
Embodiment 4C
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene base)-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine
According to the described method of embodiment 3C, with embodiment 4B alternate embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.30-1.45(m,?2?H),?1.55-1.73(m,?6?H),?1.74-1.94(m,?2?H),?1.96-2.19(m,?3?H),?3.83-3.91(m,?1?H),?3.94(s,?2?H),?4.47(s,?1?H),?7.10(td, J=8.5,?3.4?Hz,?1?H),?7.19-7.44(m,?2?H),?8.69(d, J=6.8?Hz,?1?H);?MS(ESI +)?m/ z346(M+H) +。
Embodiment 5
(1E)-N'-cyanic acid-2-(2-fluorophenyl)-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine
According to the described method of embodiment 3C, pursue ETHYLE ACETATE (the open US2006/0025614 of U.S. Patent application) alternate embodiment 3B, synthesising title compound with N-cyanic acid-2-(2-fluorophenyl) imido. 1H NMR (300 MHz, DMSO -d 6) δ ppm 1.29-1.45 (m, 2 H), 1.56-1.76 (m, 6 H), 1.76-1.93 (m, 2 H), 1.95-2.19 (m; 3 H), 3.85-3.92 (m, 1 H), 3.97 (s, 2 H), 4.47 (s, 1 H); (7.19 d, 3 H), 7.37 (d, 1 H), 8.69 (d J=6.8 Hz, 1 H); MS (ESI +) m/ z328 (M+H) +. C 19H 22FN 3The analytical calculation value of O: C, 69.70; H, 6.77; N, 12.83 measured values: C, 69.31; H, 6.87; N, 12.54.
Embodiment 6
(1E)-2-(2-chloro-pyridine-3-yl)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine
Embodiment 6A
2-(2-chloro-pyridine-3-yl) imido is by ETHYLE ACETATE
Under 0 ℃, in the solution of refrigerative 2-(2-chloro-pyridine-3-yl) acetonitrile (Synthesis (6), 528-30,1992) (1.7 g, 11.1 mmol), ethanol (1.0 mL, 16.7 mmol) and methylene dichloride (25 mL), blasted HCl gas 30 minutes.After under 4 ℃, leaving standstill 24 hours, concentrate this reaction mixture, and resistates is ground with diethyl ether.Collecting precipitation, drying obtains title compound.MS(ESI +)?m/ z199(M+H) +。
Embodiment 6B
2-(2-chloro-pyridine-3-yl)-N-cyanoimino is by ETHYLE ACETATE
Use the described method of embodiment 4B, handle embodiment 6A and cyanamide (Aldrich), obtain title compound.MS(ESI +)?m/ z224(M+H) +。
Embodiment 6C
(1E)-2-(2-chloro-pyridine-3-yl)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine
According to the described method of embodiment 3C, with embodiment 6B alternate embodiment 3B, synthesising title compound. 1H NMR (300 MHz, DMSO -d 6) δ ppm 1.30-1.47 (m, 2 H), 1.56-1.73 (m, 6 H), 1.76-1.92 (m, 2 H), 1.97-2.19 (m, 3 H), 3.90-3.98 (m, 1 H), 4.05 (s, 2 H), 4.48 (s, 1 H), 7.46 (dd, J=7.5,4.7 Hz, 1 H), 7.62 (dd, J=7.6,1.9 Hz, 1 H), 8.36 (dd, J=4.6,1.9 Hz, 1 H), 8.74 (d, J=6.4 Hz, 1 H); MS (ESI +) m/ z345 (M+H) +. C 18H 21ClN 4O 0.05H 2The analytical calculation value of O: C, 62.53; H, 6.15; N, 16.20 measured values: C, 62.13; H, 6.02; N, 16.58.
Embodiment 7
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine
Embodiment 7A
2-(4-chlorophenoxy) imido is by ethyl acetate hydrochloride
Use the described method of embodiment 4A, handle 2-(4-chlorophenoxy) acetonitrile (Aldrich), HCl gas and the ethanol that are purchased, obtain title compound.MS(ESI +)?m/ z214(M+H) +。
Embodiment 7B
2-(4-chlorophenoxy)-N-cyanoimino is by ETHYLE ACETATE
Use the described method of embodiment 4B, handle embodiment 7A and cyanamide (Aldrich), obtain title compound.MS(ESI +)?m/ z239(M+H) +。
Embodiment 7C
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine
According to the described method of embodiment 3C, with embodiment 7B alternate embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.30-1.42(m,?2?H),?1.55-1.70(m,?6?H),?1.73-1.84(m,?2?H),?1.95-2.15(m,?3?H),?3.78-3.90(m,?1?H),?4.47(s,?1?H),?4.93(s,?2?H),?6.90-7.10(m,?2?H),?7.31-7.49(m,?2?H),?8.60(d, J=5.1?Hz,?1?H);?MS(ESI +)?m/ z360(M+H) +。C 19H 22ClN 3O 20.1H 2The analytical calculation value of O: C, 63.10; H, 6.19; N, 11.62.Measured value: C, 62.82; H, 6.32; N, 11.43.
Embodiment 8
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl-prop amidine
Embodiment 8A
2-(4-chlorophenoxy)-2-methyl-prop imido acid carbethoxy hydrochloride
Use the described method of embodiment 4A, handle 2-(4-the chlorophenoxy)-2-methyl propionitrile (Maybridge), HCl gas and the ethanol that are purchased, obtain title compound.MS(ESI +)?m/ z242(M+H) +。
Embodiment 8B
2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imido acid ethyl ester
Use the described method of embodiment 3B, handle embodiment 8A and cyanamide (Aldrich), obtain title compound.MS(ESI +)?m/ z267(M+H) +。
Another preparation method of embodiment 8B
According to the method described in the preparation of N-cyanic acid-2-methyl-2-phenoxy third imido acid ethyl ester (CI-1), substitute phenol with the 4-chlorophenol, also can prepare embodiment 8B.
Embodiment 8C
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 8B alternate embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.31-1.48(m,?2?H),?1.57-1.77(m,?8?H),?1.64(s,?6?H),?1.94-2.04(m,?1?H),?2.14-2.25(m,?2?H),?3.90-4.02(m,?1?H),?4.50(s,?1?H),?6.96-7.06(m,?2?H),?7.32-7.43(m,?2?H),?7.57(d, J=6.8?Hz,?1?H);?MS(ESI +)?m/ z388(M+H) +。C 21H 26ClN 3O 20.25H 2The analytical calculation value of O: C, 64.28; H, 6.81; N, 10.71.Measured value: C, 64.53; H, 6.70; N, 10.31.
Embodiment 9
2-(4-chlorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide
Embodiment 9A
2-(4-chlorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] propionic acid amide
According to people such as Sorensen ( Bioorg. Med. Chem. Lett.2007,17,527-532) described method, synthesising title compound.
Embodiment 9B
2-(4-chlorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide
According to the described method of embodiment 1B, with embodiment 9A alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.50-1.83(m,?10?H),?1.87-2.15(m,?7?H),?2.41(s,?2?H),?2.87(s,?3?H),?4.28-4.53(m,?1?H),?7.13-7.31(m,?2?H),?7.55(dd, J=10.0,?1.9?Hz,?1?H),?9.43(d, J=7.1?Hz,?1?H);?MS(DCI+)?m/ z460(M+H) +。C 21H 27ClN 2O 3S 2The analytical calculation value: C, 57.06; H, 6.38; N, 3.17.Measured value: C, 57.16; H, 6.50; N, 3.05.
Embodiment 10
(1E)-N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
Use embodiment 2 described methods, handle embodiment 8B with (E)-4-aminoadamantan-1-sulphonamide (people such as Sorensen, Bioorg. Med. Chem. Lett.,2007,17,527-532), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.42-1.54(m,?2?H),?1.65(s,?6?H),?1.70-1.82(m,?2?H),?1.84-2.08(m,?7?H),?2.22-2.33(m,?2?H),?3.90-4.08(m,?1?H),?6.63(s,?2?H),?7.01(d, J=9.1?Hz,?2?H),?7.38(d, J=9.1?Hz,?2?H),?7.67(d, J=6.3?Hz,?1?H);?MS(ESI +)?m/ z451(M+H) +。C 21H 27ClN 4O 3The analytical calculation value of S: C-55.93; H-6.03; N-12.42.Measured value: C-56.19; H-6.05; N-12.25.
Embodiment 11
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methyl-formiate
Embodiment 11A
E-2-amino-5-carboxyl diamantane methyl ester
With E-2-amino-5-carboxyl diamantane methyl ester hydrochloride (people such as Becker, Org. Process R & D, 2008,12,1114-1118) (5 g, 20.4 mmol) are at saturated NaHCO 3Distribute between the aqueous solution (60 mL) and the methylene dichloride (100 mL).Water layer is further extracted with methylene dichloride (3 * 50 mL).Use anhydrous Na 2SO 4The dry organic extraction that merges filters, and concentrating under reduced pressure obtains title compound.MS(ESI +)?m/ z210(M+H) +。
Embodiment 11B
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methyl-formiate
Use embodiment 2 described methods, handle embodiment 8B and embodiment 11A, obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.46-1.58(m,?2?H),?1.62-1.68(m,?6?H),?1.68-1.84(m,?4?H),?1.85-1.96(m,?5?H),?2.10-2.23(m,?2?H),?3.59(s,?3?H),?3.98-4.11(m,?1?H),?6.96-7.07(m,?2?H),?7.32-7.44(m,?2?H),?7.65(d, J=6.3?Hz,?1?H);?MS(ESI +)?m/ z430(M+H) +。C 23H 28ClN 3O 3The analytical calculation value: C-64.25; H-6.56; N-9.77.Measured value: C-64.31; H-6.58; N-9.79.
Embodiment 12
2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide
Embodiment 12A
2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(1E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide
According to people such as Sorensen ( Bioorg. Med. Chem. Lett.2007,17,527-532) described method, synthesising title compound.
Embodiment 12B
2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide
According to the described method of embodiment 1B, with embodiment 12A alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.50-1.84(m,?10?H),?1.86-2.18(m,?8?H),?2.41(s,?2?H),?2.87(s,?3?H),?4.30-4.55(m,?1?H),?7.11-7.29(m,?1?H),?7.55(dd, J=10.0,?1.9?Hz,?1?H),?9.43(d, J=7.1?Hz,?1?H);?MS(DCI+)?m/ z460(M+H) +。C 21H 27ClNFO 3S 2The analytical calculation value: C, 54.94; H, 5.92; N, 3.04.Measured value: C, 54.94; H, 6.11; N, 2.98.
Embodiment 13
(1E)-2-(4-chlorophenoxy)-N'-methoxyl group-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine
Acetonitrile (20 mL) solution of embodiment 9 (200 mg, 0.45 mmol) is handled with O-methyl hydroxylamine hydrochloride (94 mg, 1.1 mmol), mercuric acetate (II) (216 mg, 0.67 mmol) and triethylamine (0.12 mL, 0.90 mmol).This reaction mixture was heated 18 hours down at 80 ℃.Then with this mixture concentrating under reduced pressure, and with resistates at saturated NaHCO 3Distribute between the aqueous solution and the ETHYLE ACETATE.With the dry (MgSO of the organic layer that merges 4), filter, concentrate.(hexane-ETHYLE ACETATE 1:2), obtains title compound with residue purified by chromatography. 1H?NMR(500?MHz,?DMSO -d 6)δ?ppm?1.36-1.70(m,?10?H),?1.72-2.07(m,?9?H),?2.73-2.92(m,?3?H),?3.70(s,?3?H),?4.14(d, J=10.1?Hz,?1?H),?5.32(d, J=10.1?Hz,?1?H),?6.95-7.04(m,?2?H),?7.25-7.39(m,?2?H);?MS(DCI+)?m/ z455(M+H) +。
Embodiment 14
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide
Embodiment 14A
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid
In THF (2 mL), methyl alcohol (4 mL) and water (4 mL) solution of embodiment 11 (0.48 g, 1.1 mmol), add the 5N NaOH aqueous solution (1.1 mL, 5.6 mmol).After at room temperature stirring 16 hours, this reaction mixture is concentrated into half volume, the pH value is adjusted to～5, and this mixture is extracted with ETHYLE ACETATE (3 * 15 mL).Use anhydrous Na 2SO 4The dry organic extraction that merges filters, and concentrating under reduced pressure obtains title compound bullion form, and it just can use without additional purification.MS(ESI +)?m/ z416(M+H) +。
Embodiment 14B
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide
To embodiment 14A (0.37 g; 0.9 add 1-hydroxyl-benzotriazole hydrate (0.16 g in methylene dichloride mmol) (10 mL) solution; 1.1 mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (0.25 g; 1.3 mmol) with 30% ammonium hydroxide aqueous solution (1.0 mg, 8.9 mmol).At room temperature stirred this reaction mixture 16 hours, water (10mL) cancellation then.Water layer is extracted with methylene dichloride (3 * 20 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrates.Resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, 0-50% methanol/ethyl acetate (1/10) is in hexane), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.45-1.55(m,?2?H),?1.62-1.68(m,?6?H),?1.67-1.78(m,?4?H),?1.82-1.94(m,?5?H),?2.08-2.20(m,?2?H),?3.98-4.06(m,?1?H),?6.74(s,?1?H),?6.96-7.06(m,?3?H),?7.33-7.45(m,?2?H),?7.62(d, J=6.7?Hz,?1?H);?MS(ESI +)?m/ z415(M+H) +。C 27H 27ClN 4O 2The analytical calculation value: C-63.68, H-6.56, N-13.50.Measured value: C-63.35; H-6.53; N-13.06.
Embodiment 15
1-(3-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] the tetramethylene carbonamidine
Embodiment 15A
1-(3-chlorophenoxy) cyclobutane formate ethyl ester
To the N of 3-chlorophenol (7.5 g, 58.0 mmol), add cesium carbonate (28.3 g, 87 mmol) in dinethylformamide (125 mL) solution, then add 1-bromine cyclobutane formate ethyl ester (9.8 mL, 58.0 mmol).With this reaction mixture 55 ℃ of following stirred overnight.Solids removed by filtration, and filtrate decompression is concentrated.(silicon-dioxide, heptane/ETHYLE ACETATE 7:1), obtain 1-(3-chlorophenoxy) cyclobutane formate ethyl ester with purified.MS(ESI +)?m/ z255(M+H) +。
Embodiment 15B
1-(3-chlorophenoxy) NSC 4535
At room temperature, lithium hydroxide monohydrate (1.7 g, 40.3 mmol) is joined in the THF (320 mL) and water (160 mL) suspension-s of embodiment 15A (4.7 g, 13.4 mmol).With this reaction mixture 55 ℃ of following stirred overnight.Should react concentrating under reduced pressure, remove THF, through adding 1M HCl acidified aqueous solution to pH～3, cooling simultaneously.Filter collecting precipitation, dried overnight in comprising the moisture eliminator of KOH.Use the heptane recrystallization, obtain title compound.MS(ESI +)?m/ z227(M+H) +。
Embodiment 15C
(1E)-2-(3-chlorophenoxy)-N-[(E)-5-hydroxyl-2-adamantyl]-the 2-methyl propanamide
To E-2-amino-5-hydroxyadamantane (people such as Jaroskova, Tetrahedron Letters2006,47 (46), the 8063-8067) N of (0.25 g, 1.5 mmol); Add embodiment 15B (0.34 g, 1.5 mmol), 2-(1H-benzo [d] [1,2 in dinethylformamide (10 mL) solution; 3] triazol-1-yl)-1,1,3; 3-tetramethyl-isourea a tetrafluoro borate (0.72 g, 2.2 mmol) and diisopropylethylamine (0.78 mL, 4.5 mmol).At room temperature stirred this reaction mixture 16 hours, this reaction mixture of water (10 mL) cancellation then.Separate each layer that obtains, and water layer is extracted with ETHYLE ACETATE (3 * 20 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrates.Resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, 0-80% ethanol/methylene (1/10) is in methylene dichloride), obtain title compound.MS(ESI +)?m/ z376(M+H) +。
Embodiment 15D
1-(3-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] the tetramethylene carbonamidine
According to embodiment 1B and the described method of embodiment 1C, with embodiment 15B alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.17-1.38(m,?2?H),?1.48-1.70(m,?7?H),?1.80-2.04(m,?6?H),?2.05-2.17(m,?2?H),?2.82-2.95(m,?2?H),?3.89-4.01(m,?1?H),?4.44(s,?1?H),?6.74-6.91(m,?2?H),?7.07(d, J=7.6?Hz,?1?H),?7.32(t, J=8.2?Hz,?1?H),?7.73-7.86(m,?1?H);?MS(ESI +)?m/ z400(M+H) +。
Embodiment 16
(E)-4-[(2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the sulfo-propionyl group) amino] diamantane-1-methyl-formiate
Embodiment 16A
(E)-4-[(2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third carbonyl) amino] diamantane-1-methyl-formiate
According to people such as Patel ( Bioorg. Med. Chem. Lett.2007,17,750-755) described method, synthesising title compound.
Embodiment 16B
(E)-4-[(2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the sulfo-propionyl group) amino] diamantane-1-methyl-formiate
According to the described method of embodiment 1B, with embodiment 16A alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.35-1.66(m,?10?H),?1.74-1.96(m,?7?H),?2.15(d, J=2.4?Hz,?2?H),?3.58(s,?3?H),?4.16-4.37(m,?1?H),?4.63(s,?2?H),?7.57-7.69(m,?2?H),?7.70-7.82(m,?2?H),?9.01(d, J=7.1?Hz,?1?H);?MS(DCI+)?m/ z460(M+H) +。
Embodiment 17
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate
According to the described method of embodiment 1C, with embodiment 16 alternate embodiment 1B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.42-1.59(m,?4?H),?1.65(s,?6?H),?1.72-1.96(m,?7?H),?2.08(d, J=2.0?Hz,?2?H),?3.58(s,?3?H),?3.98(d, J=6.8?Hz,?1?H),?4.70(s,?2?H),?7.51(d, J=7.1?Hz,?1?H),?7.57-7.69(m,?2?H),?7.71-7.82(m,?2?H);?MS(DCI+)?m/ z478(M+H) +。C 25H 30N 3F 3O 30.75H 2The analytical calculation value of O: C, 61.15; H, 6.47; N, 8.56.Measured value: C, 61.24; H, 6.22; N, 8.20.
Embodiment 18
(1E)-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine
According to the described method of embodiment 1C, with embodiment 12 alternate embodiment 1B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.52-1.64(m,?1?H),?1.69(s,?6?H),?1.75-2.19(m,?10?H),?2.33(s,?2?H),?2.86(s,?3?H),?4.08(s,?1?H),?7.17-7.36(m,?2?H),?7.58(dd, J=8.5,?3.0?Hz,?1?H),?7.96(d, J=6.7?Hz,?1?H);?MS(DCI+)?m/ z478(M+H) +。
Embodiment 19
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine
According to the described method of embodiment 1C, with embodiment 9 alternate embodiment 1B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.44-1.59(m,?1?H),?1.66(s,?6?H),?1.84-2.14(m,?10?H),?2.31(s,?2?H),?2.78-2.94(m,?3?H),?4.03(d, J=7.1?Hz,?1?H),?6.96-7.07(m,?2?H),?7.33-7.46(m,?2?H),?7.68(d, J=6.4?Hz,?1?H);?MS(DCI+)?m/ z450(M+H) +。C 22H 28N 3O 3The analytical calculation value of S: C, 58.72; H, 6.27; N, 8.59.Measured value: C, 58.43; H, 6.43; N, 8.59.
Embodiment 20
N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy) phenoxy] thiopropionamide
Embodiment 20A
N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy) phenoxy] propionic acid amide
According to people such as Sorensen (Bioorg. Med. Chem. Lett. 2007,17,527-532) described method, synthesising title compound.
Embodiment 20B
N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy) phenoxy] thiopropionamide
According to the described method of embodiment 1B, with embodiment 20A alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.42-1.62(m,?3?H),?1.66(s,?6?H),?1.80-2.10(m,?8?H),?2.31(s,?2?H),?4.24-4.48(m,?1?H),?6.63(s,?2?H),?7.07(d, J=8.3?Hz,?1?H),?7.13-7.22(m,?1?H),?7.30-7.39(m,?1?H),?7.44(d, J=8.3?Hz,?1?H),?9.11(d, J=7.1?Hz,?1?H);?MS(DCI+)?m/ z493(M+H) +。
Embodiment 21
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the sulfo-propionyl group) amino] diamantane-1-methyl-formiate
Embodiment 21A
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } propionyl group) amino] diamantane-1-methyl-formiate
According to people such as Becker ( Org. Process R & D, 2008,12,1114-1118) described method, synthesising title compound.
Embodiment 21B
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the sulfo-propionyl group) amino] diamantane-1-methyl-formiate
According to the described method of embodiment 1B, with embodiment 21A alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.22-1.38(m,?6?H),?1.68(q, J=13.0?Hz,?4?H),?1.81-2.06(m,?7?H),?2.19(s,?2?H),?3.32(s,?6?H),?3.52-3.76(m,?5?H),?4.24-4.42(m,?1?H),?6.98(d, J=9.2?Hz,?1?H),?7.81(dd, J=9.2,?2.4?Hz,?1?H),?8.42(d, J=1.7?Hz,?1?H),?10.23(d, J=7.8?Hz,?1?H);?MS(DCI+)?m/ z525(M+H) +。
Embodiment 22
3-(4-chloro-phenyl-)-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine
Embodiment 22A
3-(4-chloro-phenyl-)-2,2-dimethyl-propionitrile
At 0-5 ℃, (2 M in THF, add isopropyl cyanide (2.0 mL, 21.9 mmol) in THF Aldrich) (100 mL) solution for 11.0 mL, 21.9 mmol to lithium diisopropylamine.After stirring 30 minutes, under uniform temp, add THF (10 mL) solution of 1-(brooethyl)-4-chlorobenzene (3.0 g, 14.6 mmol).After at room temperature stirring 2 hours, (50 mL) handles this reaction mixture with 10% hydrochloric acid, and concentrating under reduced pressure is removed THF.Extract enriched material with ETHYLE ACETATE (3 * 50 mL).The organic extraction that merges is used NaHCO successively 3Anhydrous Na is used in the aqueous solution (50 mL) and salt solution (50 mL) washing 2SO 4Drying is filtered concentrating under reduced pressure.Then resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, the 0-30% ethyl acetate/hexane), obtain title compound.MS(DCI +)?m/ z211(M+NH 4) +。
Embodiment 22B
3-(4-chloro-phenyl-)-2,2-dimethyl propylene imido acid carbethoxy hydrochloride
Use the described method of embodiment 4A, handle embodiment 22A, HCl gas and ethanol, obtain title compound.MS(ESI +)?m/ z240(M+H) +。
Embodiment 22C
3-(4-chloro-phenyl-)-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine
With E-2-amino-5-hydroxyadamantane (people such as Jaroskova, Tetrahedron Letters2006,47 (46), 8063-8067) (59 mg, 0.36 mmol) and 3-(4-chloro-phenyl-)-2, the mixture of 2-dimethyl propylene imido acid ethyl ester (obtaining after the supercarbonate washing embodiment 22B) (85 mg, 0.36 mmol) stirred 16 hours down at 120 ℃.With this reaction mixture cooling; Be dissolved in the methylene dichloride (2 mL); ((on the 30mm * 75mm), use the gradient of 20% to 95% acetonitrile/10 mM ammonium acetates, with preparation HPLC purifying through 10 minutes at Phenomenex Luna C8 (2) 5 um 100 AXIA posts; Flow velocity 50 mL/ minutes), title compound is provided. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.09-1.19(m,?2?H),?1.37(s,?6?H),?1.40-1.51(m,?2?H),?1.66-1.82(m,?4?H),?1.99-2.12(m,?7?H),?3.00(s,?2?H),?3.42-3.56(m,?1?H),?4.11(s,?1?H),?7.11(d, J=8.3?Hz,?2?H),?7.17-7.28(m,?2?H);?MS(ESI +)?m/ z361(M+H) +。
Embodiment 23
(1E)-3-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine
Embodiment 23A
3-(4-chloro-phenyl-)-N-cyanic acid-2,2-dimethyl propylene imido acid ethyl ester
Use the described method of embodiment 3B, handle embodiment 22A and cyanamide (Aldrich), obtain title compound.MS(ESI +)?m/ z265(M+H) +。
Embodiment 23B
(1E)-3-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine
According to the described method of embodiment 3C, with embodiment 23A alternate embodiment 3B, synthesising title compound. 1H NMR (300 MHz, DMSO -d 6) δ ppm 1.18-1.32 (m, 4 H), 1.35 (s, 6 H), 1.50-1.70 (m, 6 H), 1.80-1.91 (m; 1 H), 1.94-2.04 (m, 2 H), 3.11 (s, 2 H), 3.77-3.87 (m, 1 H); (4.44 s, 1 H), 6.36 (s, 1 H), 7.13 (d J=8.3 Hz, 2 H), 7.35 (d, J=8.3 Hz, 2 H); MS (ESI +) m/ z386 (M+H) +. C 21H 28ClN 3The analytical calculation value of O 0.2 ETHYLE ACETATE: C-67.86; H-7.39; N-10.41. measured value C-67.48; H-7.51; N-10.17.
Embodiment 24
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid
Methyl alcohol with embodiment 17 (0.35 g, 0.7 mmol): THF (1:1,10 mL) solution is handled with 2N NaOH (0.5 mL, 3.5 mmol), and stirs 30 hours.This reaction mixture of vacuum concentration, dilute with water is acidified to pH～5, then uses ethyl acetate extraction.Use the brine wash organic layer, dry (MgSO 4), concentrate, obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.32-1.61(m,?3?H),?1.65(s,?6?H),?1.71-1.96(m,?8?H),?2.06(s,?2?H),?3.89-4.04(m,?1?H),?4.70(s,?2?H),?7.51(d, J=7.1?Hz,?1?H),?7.63(d, J=8.3?Hz,?2?H),?7.69-7.87(m,?2?H),?12.12(s,?1?H);?MS(DCI+)?m/ z464(M+H) +。
Embodiment 25
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide
CH with embodiment 24 (0.34 g, 0.72 mmol) 2Cl 2(20 mL) solution is handled with 1H-benzo [d] [1,2,3] triazole-1-alcohol hydrate (0.12 g, 0.8 mmol), then uses N 1-((ethyl imino-) methylene radical)-N 3, N 3-dimethylpropane-1,3-diamine hydrochloride (0.17 g, 0.91 mmol) is handled, and reaction mixture was stirred 1 hour.Add 30% NH then 4The OH aqueous solution (0.5 mL, 3.6 mmol), and reaction mixture at room temperature stirred 18 hours.This reaction mixture of vacuum concentration, and resistates distributed between ETHYLE ACETATE and water.The organic layer that merges with brine wash then, dry (MgSO 4), concentrate.Use purification by flash chromatography, use 0-18% ethanol/ETHYLE ACETATE, title compound is provided as elutriant. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.39-1.58(m,?4?H),?1.61-1.90(m,?14?H),?2.04(s,?2?H),?3.94(s,?1?H),?4.71(s,?1?H),?6.73(s,?1?H),?6.99(s,?1?H),?7.50(d, J=7.1?Hz,?1?H),?7.59-7.69(m,?2?H),?7.70-7.81(m,?2?H);?MS(DCI+)?m/ z463(M+H) +。C 25H 30N 3F 3O 30.2 H 2The analytical calculation value of O: C, 61.84; H, 6.36; N, 12.02.Measured value: C, 61.64; H, 6.34; N, 11.97.
Embodiment 26
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the sulfo-propionyl group) amino] diamantane-1-formic acid
(E)-4-{2-methyl-2-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-propionyl group is amino }-diamantane-1-formic acid (0.085 mmol; U.S. Patent application 2005/0277647), the stirred solution of Lawesson's reagent (0.085 mmol) and toluene is heated to 120 ℃, kept 2 hours.This reaction mixture is cooled to 23 ℃, and vacuum concentration.The resistates that obtains is filtered through short quick silica gel plug, at first use the methylene dichloride wash-out, then use eluent ethyl acetate.Confirm that with LCMS the fraction of collecting carries out vacuum concentration for needed product, and further use reversed-phase HPLC purifying (YMC ODS Guardpak post, the gradient of acetonitrile/10 mM ammonium acetate-water), title compound is provided. 1H?NMR(400?MHz,?DMSO- d 6)δ8.41(s,?1H),?7.80(m,?1H),?7.72(m,?1H),?6.97(d,?J=8?Hz,?1H),?3.81(m,?1H),?3.66(m,?4H),?2.54(m,?4H),?2.07-1.69(m,?11H),?1.65-1.50(m,?2H),?1.13(s,?6H);?MS(APCI)?m/z?511(M+H) +。
Embodiment 27
(1E)-N'-cyanic acid-N-[(E)-5-cyanic acid-2-adamantyl]-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third amidine
Product (73 mg with embodiment 25; 0.158 two mmol) alkane/pyridine (1.5 mL/0.15 mL) solution is cooled to 0 ℃; And handle with trifluoroacetic anhydride (0.022 mL, 0.158 mmol).At room temperature stirred this reaction mixture 18 hours, vacuum concentration then distributes between ETHYLE ACETATE and salt solution.Water (2 x, 30 mL) washing organic layer, dry (MgSO 4), concentrate.With reversed-phase HPLC method purifying, (gradient of 30mm * 75mm) and 10-100% acetonitrile and 10 mM ammonium acetate/water provides title compound to use Phenomenex Luna C8 (2) 5 um 100 AXIA posts. 1H?NMR(300?MHz,?CDCl 3)δ?ppm?1.43-1.63(m,?9?H),?1.84-2.28(m,?10?H),?3.90-4.09(m,?1?H),?4.58(s,?2?H),?6.98(d, J=7.8?Hz,?1?H),?7.45(d, J=8.1?Hz,?2?H),?7.63(d, J=8.1?Hz,?2?H);?MS(DCI+)?m/z?445(M+H) +。
Embodiment 28
(E)-4-((1E)-and N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate
(E)-4-({ 2-[(4-methoxybenzyl) oxygen base]-2-methylpropionyl } amino) diamantane-1-methyl-formiate, according to people such as Patel ( Bioorg. Med. Chem. Lett.2007,17,750-755) described method, synthesising title compound.
Embodiment 28B
(E)-4-({ 2-[(4-methoxybenzyl) oxygen base]-2-methyl sulfo-propionyl group } amino) diamantane-1-methyl-formiate
In THF (25 mL) solution of embodiment 28A (2.1g, 5 mmol), add Lawesson reagent (2.04 mg, 5 mmol), and reaction mixture was heated 4 hours down at 50 ℃.With this reaction mixture concentrating under reduced pressure, and with resistates at saturated NaHCO 3And distribute between the ETHYLE ACETATE.With the dry (MgSO of the organic layer that merges 4), filter, concentrate.With purification by flash chromatography resistates (SiO 2, the 0-40% ethyl acetate/hexane), title compound is provided.MS(DCI+)?m/z?432(M+H) +。
Embodiment 28C
(E)-4-((1E)-and N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate
According to the described method of embodiment 1C, with embodiment 28B alternate embodiment 1B, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.33-1.56(m,?4?H),?1.63(s,?6?H),?1.70-2.13(m,?9?H),?3.58(s,?3?H),?3.67-3.79(m,?3?H),?3.97(d, J=4.4?Hz,?1?H),?4.50(s,?2?H),?6.90-7.01(m,?2?H),?7.28-7.39(m,?2?H),?7.55(d, J=7.5?Hz,?1?H);?MS(DCI+)?m/z?440(M+H) +。
Embodiment 29
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate
With embodiment 21 (366 mg; 0.7 mmol) in methylene dichloride (8 mL) with methylene dichloride (1 mL, the 1 mmol) solution-treated of 1 mole of triethyl oxygen
Figure 465648DEST_PATH_IMAGE010
a tetrafluoro borate.Stirred this reaction mixture 18 hours down at 45 ℃.This reaction mixture of vacuum concentration, and resistates is dissolved in the ethanol, then use cyanamide (120 mg, 2.8 mmol) and triethylamine (0.3 mL, 2.2 mmol) to handle.This reaction mixture was heated 18 hours down at 80 ℃, then vacuum concentration.Resistates is distributed between ETHYLE ACETATE and water.Dry (MgSO 4) organic layer, vacuum concentration.With purification by flash chromatography (SiO 2, 0-10% ethanol/ETHYLE ACETATE), title compound is provided. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.28-1.43(m,?6?H),?1.51-2.20(m,?13?H),?2.54-2.64(m,?4?H),?3.60(s,?3?H),?3.66(s,?4?H),?4.14(s,?1?H),?6.99(d, J=9.1?Hz,?1?H),?7.81(dd, J=8.9,?2.6?Hz,?1?H),?8.42(s,?1?H),?8.67(d, J=5.6?Hz,?1?H);?MS(DCI+)?m/z?533(M+H) +。
Embodiment 30
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid
According to the described method of embodiment 14A, with embodiment 29 alternate embodiments 11, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.12-1.33(m,?6?H),?1.53(d, J=12.5?Hz,?2?H),?1.64-2.10(m,?12?H),?2.50-2.63(m,?4?H),?3.64(s,?4?H),?3.81(s,?1?H),?6.98(d, J=8.8?Hz,?1?H),?7.26(d, J=8.5?Hz,?1?H),?7.80(dd, J=9.2,?2.7?Hz,?1?H),?8.41(s,?1?H);?MS(DCI+)?m/z?519(M+H) +。
Embodiment 31
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide
According to the described method of embodiment 14B, with embodiment 30 alternate embodiment 14A, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.35(s,?6?H),?1.50-2.18(m,?13?H),?2.52-2.66(m,?4?H),?3.67(s,?4?H),?4.11(s,?1?H),?6.74(s,?1?H),?6.99(d,?J=9.2?Hz,?2?H),?7.81(dd,?J=9.2,?2.4?Hz,?1?H),?8.42(s,?1?H),?8.66(d,?J=7.5?Hz,?1?H);?MS(DCI+)?m/z?518(M+H)+。C 26H 34F3N 7The analytical calculation value of O: C, 60.34; H, 6.65; N, 18.94.Measured value: C, 60.34; H, 6.65; N, 18.55.
Embodiment 32
6-(4,4-dimethyl--1-[(E)-5-(methyl sulphonyl)-2-adamantyl]-5-sulfo-tetramethyleneimine-3-yl } methoxyl group) the cigarette nitrile
Embodiment 32A
6-(4,4-dimethyl--1-[(E)-5-(methyl sulphonyl)-2-adamantyl]-5-oxo-pyrrolidine-3-yl } methoxyl group) the cigarette nitrile
According to the method described in the following reference, synthesising title compound: people such as Yeh, Bioorg. Med. Chem. Lett.2006,16,5555-5560.
Embodiment 32B
6-(4,4-dimethyl--1-[(E)-5-(methyl sulphonyl)-2-adamantyl]-5-sulfo-tetramethyleneimine-3-yl } methoxyl group) the cigarette nitrile
According to embodiment 28 described methods, with embodiment 32A alternate embodiment 28A, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?0.97-1.13(m,?3?H),?1.18-1.39(m,?3?H),?1.61(t, J=14.7?Hz,?2?H),?1.75-2.23(m,?10?H),?2.76-2.97(m,?3?H),?3.87(dd, J=10.9,?8.5?Hz,?1?H),?4.13(dd, J=11.1,?7.9?Hz,?1?H),?4.28-4.64(m,?3?H),?6.85(d, J=8.7?Hz,?1?H),?8.24(dd, J=8.7,?2.8?Hz,?1?H),?8.72(d, J=2.4?Hz,?1?H),?9.51(s,?1?H),?9.84(s,?1?H);?MS(DCI+)?m/z?474(M+H) +。
Embodiment 33
(2Z)-and 4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--1-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] tetramethyleneimine-2-subunit cyanamide
According to embodiment 29 described methods, with embodiment 32 alternate embodiments 21, synthesising title compound. 1H?NMR(400?MHz,?DMSO- d 6)δ?ppm?1.23-1.36(m,?3?H),?1.52(s,?3?H),?1.56(s,?1?H),?1.68-2.25(m,?12?H),?2.43(s,?2?H),?2.57-2.74(m,?1?H),?3.64-4.06(m,?4?H),?4.35-4.64(m,?2?H),?7.04(d, J=8.5?Hz,?1?H),?8.18(dd, J=8.7,?2.3?Hz,?1?H),?8.72(d, J=2.1?Hz,?1?H);?MS(DCI+)?m/z?482(M+H) +。
Embodiment 34
(3S)-1-[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl]-N-cyclohexyl piperidines-3-thioformamide
According to the described method of embodiment 1B, with (S)-1-(3-chloro-2-Methyl benzenesulfonyl)-N-cyclohexyl piperidines-3-methane amide alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.05-1.36(m,?5?H),?1.45-1.95(m,?9?H),?2.57-2.68(m,?1?H),?2.59(s,?3?H),?2.78(t,?1?H),?2.99(t, J=11.5?Hz,?1?H),?3.48-3.70(m,?2?H),?4.01-4.33(m,?1?H),?7.46(t, J=7.9?Hz,?1?H),?7.80(t, J=8.3?Hz,?2?H),?9.88(d, J=7.5?Hz,?1?H);?MS(ESI +)?m/ z415(M+H) +。
Embodiment 35
(3S)-1-[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl]-N'-cyanic acid-N-cyclohexyl piperidines-3-carbonamidine
To embodiment 34 (200 mg; 0.48 add triethyl oxygen a tetrafluoro borate (0.96 mL in methylene dichloride mmol) (15 mL) solution; 0.96 mmol; 1 M is in methylene dichloride), and with this mixture stirred overnight at room temperature.Then this reaction mixture is heated to 50 ℃, kept again 3 days, continue simultaneously to stir.Cool off this reaction mixture, concentrate, in ether, grind.With the product that obtains be dissolved in ethanol (2 mL) and cyanamide (61 mg, 1.4mmol) in, and adding triethylamine (0.2 mL, 1.4 mmol).After 80 ℃ are stirred 16 hours down, cool off this reaction mixture, water (10mL) dilutes, and extracts with ETHYLE ACETATE (3 x, 10 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure.Resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, the 0-100% ethyl acetate/hexane). 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.04-1.34(m,?5?H),?1.44-1.91(m,?9?H),?2.60(s,?3?H),?2.60-2.70(m,?1?H),?2.83-2.98(m,?1?H),?3.08(t, J=11.4?Hz,?1?H),?3.64(t,?3?H),?7.47(t, J=8.3?Hz,?1?H),?7.80(dd, J=8.1,?1.0?Hz,?1?H),?7.83-7.89(m,?1?H),?8.31(d, J=7.5?Hz,?1?H);?MS(ESI +)?m/ z423(M+H) +。C 20H 27ClN 4O 2The analytical calculation value of S: C, 56.79; H, 6.43; N, 13.29.Measured value: C, 56.42; H, 6.41; N, 12.98.
Embodiment 36
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid
This paper has described another preparation method of embodiment 14A.To embodiment 14B (50 mg; 0.12 mmol) 1; Add 5M hydrochloric acid/water (0.5 mL, 2.5 mmol) in 4-two
Figure 786088DEST_PATH_IMAGE007
alkane (0.5 mL) solution.After 60 ℃ are stirred 6 hours down, cool off this reaction mixture, water (5mL) dilutes, and extracts with ETHYLE ACETATE (2 x, 10 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure.(, obtain title compound with preparation HPLC purifying resistates in Phenomenex Luna C8 (2) 5 um 100 AXIA posts (on the 30mm * 75mm), use the gradient of 10-95% (acetonitrile/0.1% trifluoroacetic acid-water), flow velocity 50 mL/min were through 10 minutes). 1H?NMR(500?MHz,?DMSO -d 6)δ?ppm?1.46-1.57(m,?2?H),?1.65(s,?6?H),?1.69-1.77(m,?2?H),?1.77-1.82(m,?2?H),?1.84-1.93(m,?5?H),?2.11-2.22(m,?2?H),?3.95-4.08(m,?1?H),?7.01(d, J=8.8?Hz,?2?H),?7.38(d, J=8.8?Hz,?2?H),?7.64(d, J=6.1?Hz,?1?H),?12.13(s,?1?H);?MS(ESI +)?m/ z416(M+H) +。
Embodiment 37
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-5-cyanic acid-2-adamantyl]-2-methyl-prop amidine
According to the described method of embodiment 3C, use E-4-amino-diamantane-1-nitrile (International Publication WO applied on October 18th, 2007/118185,2007) and embodiment 8B to substitute E-2-amino-5-hydroxyadamantane and embodiment 3B, synthesising title compound respectively. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.50-1.61(m,?2?H),?1.65(s,?6?H),?1.68-1.79(m,?2?H),?1.85-1.92(m,?1?H),?1.96-2.00(m,?2?H),?2.07-2.13(m,?4?H),?2.15-2.22(m,?2?H),?4.04(d,?1?H),?6.99(dt,?2?H),?7.34-7.43(m,?2?H),?7.63(d, J=6.1?Hz,?1?H);?MS(ESI +)?m/ z397(M+H) +。C 22H 26ClN 4The analytical calculation value of O: C, 66.57; H, 6.35; N, 14.12.Measured value: C, 66.39; H, 6.26; N, 14.22.
Embodiment 38
(1E)-and 2-(4-chlorophenoxy)-N'-cyanic acid-N-six hydrogen-2,5-first bridge pentalene-3a (1H)-Ji-2-methyl-prop amidine
3-is fallen mixture in ethanol (2 mL) of adamantanamine hydrochloride (100 mg, 0.58 mmol), triethylamine (0.24 mL, 1.73 mmol) and embodiment 8B (184 mg, 0.69 mmol), stirred 16 hours down at 80 ℃.Cool off this reaction mixture then, concentrate, use saturated NaHCO 3The aqueous solution (10mL) dilution.Aqueous mixture is extracted with ETHYLE ACETATE (3 x, 20 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure.With preparation HPLC purifying resistates (at Phenomenex Luna C8 (2) 5 um 100 AXIA posts (on the 30mm * 75mm); Use the gradient of 50-95% (acetonitrile/10 mM trifluoroacetic acid-water); Flow velocity 50 mL/min were through 10 minutes), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.48-1.58(m,?4?H),?1.64(s,?6?H),?1.85-2.16(m,?6?H),?2.19-2.30(m,?2?H),?2.58(t, J=6.8?Hz,?1?H),?6.96(dt,?2?H),?7.37(dt,?2?H),?8.06(s,?1?H);?MS(ESI +)?m/ z358(M+H) +。
Embodiment 39
(1E)-and N-[(4s)-1-aza-tricycle [3.3.1.1 3,7] last of the ten Heavenly stems-the 4-yl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
With l-aza-tricycle [3.3.1.1 3,7) last of the ten Heavenly stems-mixture in ethanol (2 mL) of 4s-amine dihydrochloride (Synthesis, 11,1080-2,1992) (80 mg, 0.36 mmol), triethylamine (0.15 mL, 1.1 mmol) and embodiment 8B (142 mg, 0.53 mmol), stirred 16 hours down at 80 ℃.Cool off this reaction mixture then, concentrate, use saturated NaHCO 3The aqueous solution (10mL) dilution.Aqueous mixture is extracted with ETHYLE ACETATE (3 x, 20 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure.(, obtain title compound with preparation HPLC purifying resistates in Phenomenex Luna C8 (2) 5 um 100 AXIA posts (on the 30mm * 75mm), use the gradient of 10-95% (acetonitrile/0.1% trifluoroacetic acid-water), flow velocity 50 mL/min were through 10 minutes). 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.20-1.31(m,?3?H),?1.69(s,?6?H),?1.73-2.01(m,?4?H),?3.18-3.63(m,?6?H),?4.19-4.31(m,?1?H),?6.96-7.03(m,?2?H),?7.32-7.43(m,?2?H),?7.87(d, J=5.4?Hz,?1?H);?MS(ESI +)?m/ z373(M+H) +。
Embodiment 40
N-1-azabicyclo [2.2.2] oct-3-yl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
According to embodiment 39 described methods, substitute l-aza-tricycle [3.3.1.1 with rubane-3-amine dihydrochloride (Aldrich) 3,7) last of the ten Heavenly stems-4s-amine dihydrochloride, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.18-1.31(m,?1?H),?1.59-1.73(m,?6?H),?1.72-1.99(m,?3?H),?2.23-2.37(m,?1?H),?3.09-3.79(m,?6?H),?4.28-4.53(m,?1?H),?6.96-7.06(m,?2?H),?7.34-7.45(m,?2?H),?8.66-8.84(m,?1?H);?MS(ESI +)?m/ z347(M+H) +。
Embodiment 41
2-(4-chlorophenoxy)-N'-cyanic acid-N-encircles octyl group-2-methyl-prop amidine
According to the described method of embodiment 3C, substitute E-2-amino-5-hydroxyadamantane and embodiment 3B, synthesising title compound respectively with cyclooctylamine (Aldrich) and embodiment 8B. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.37-1.57(m,?7?H),?1.59(s,?6?H),?1.61-1.79(m,?7?H),?4.02-4.18(m,?1?H),?6.94(d, J=9.2?Hz,?2?H),?7.37(d, J=9.2?Hz,?2?H),?8.43(d, J=8.1?Hz,?1?H);?MS(ESI +)?m/ z348(M+H) +。C 19H 26ClN 3The analytical calculation value of O: C, 65.60; H, 7.53; N, 12.08.Measured value: C, 65.70; H, 7.35; N, 11.97.
Embodiment 42
N-[outer-two rings [2.2.1] heptan-2-yl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
According to the described method of embodiment 3C, substitute E-2-amino-5-hydroxyadamantane and embodiment 3B, synthesising title compound respectively with amino norbornane (Aldrich) of outer-2-and embodiment 8B. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.03-1.23(m,?3?H),?1.35-1.50(m,?3?H),?1.56-1.62(m,?6?H),?1.61-1.66(m,?2?H),?2.18-2.23(m,?1?H),?2.24-2.33(m,?1?H),?3.68-3.83(m,?1?H),?6.88-7.00(m,?2?H),?7.32-7.44(m, J=9.2?Hz,?2?H),?8.13(d, J=5.8?Hz,?1?H);?MS(ESI +)?m/ z332(M+H) +。C 18H 22ClN 3The analytical calculation value of O: C, 65.15; H, 6.68; N, 12.66.Measured value: C, 65.18; H, 6.91; N, 12.43.
Embodiment 43
(1E)-N-1-adamantyl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
According to the described method of embodiment 3C, substitute E-2-amino-5-hydroxyadamantane and embodiment 3B, synthesising title compound respectively with 1-amantadine (Aldrich) and embodiment 8B. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.60-1.68(m,?6?H),?1.63(s,?6?H),?2.01-2.13(m,?9?H),?6.94-7.04(m,?2?H),?7.14(s,?1?H),?7.33-7.44(m,?2?H);?MS(ESI +)?m/ z372(M+H) +。C 21H 26ClN 3The analytical calculation value of O: C, 67.82; H, 7.05; N, 11.30.Measured value: C, 67.83; H, 6.87; N, 11.09.
Embodiment 44
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine
Embodiment 44A
2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] propionic acid amide
According to the method described in the following reference, synthesising title compound: Sorensen, B. waits the people, Bioorg. Med. Chem. Lett. 2007,17,527-532.MS(DCI+)?m/ z410(M+H) +。
Embodiment 44B
2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] thiopropionamide
According to the described method of embodiment 1B, with embodiment 44A alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.43-1.79(m,?10?H),?1.83-2.20(m,?7?H),?2.39(s,?2?H),?2.87(s,?3?H),?4.32-4.49(m,?1?H),?7.02-7.24(m,?3?H),?7.22-7.45(m,?1?H),?9.42(d, J=7.1?Hz,?1?H);?MS(DCI+)?m/ z426(M+H) +。
Embodiment 44C
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine
At room temperature; With embodiment 44B (60 mg; 0.14 methylene dichloride mmol) (3 mL) solution is with triethyl oxygen
Figure 78529DEST_PATH_IMAGE010
a tetrafluoro borate (the 1 M solution that is purchased; In THF, 0.21 mL, 0.21 mmol) dropwise handle.This reaction mixture was stirred 16 hours down at 45 ℃, then vacuum concentration.(3 mL) joins in the thioimines hydrochlorate with ethanol, and this mixture is handled with cyanamide (24 mg, 0.57 mmol) and triethylamine (43 mg, 0.42 mmol).With this reaction mixture 80 ℃ of heated overnight.With reversed-phase HPLC method purifying, use Phenomenex Luna C8, (gradient of 30mm * 75mm) and 10-100% acetonitrile and 10 mM ammonium acetate/water provides title compound to 5 μ M, 100 AXIA posts. 1H?NMR(500?MHz,?CDCl 3)δ?ppm?1.57-1.81(m,?6?H),?1.87(d, J=13.4?Hz,?2?H),?2.00-2.32(m,?9?H),?2.40(s,?2?H),?2.68-2.86(m,?3?H),?4.19(s,?1?H),?7.01-7.23(m,?4?H),?7.92(d, J=6.7?Hz,?1?H);?MS(DCI+)?m/ z434(M+H) +。
Embodiment 45
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine
Embodiment 45A
2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] propionic acid amide
According to the method described in the following reference, synthesising title compound: Sorensen, B. waits the people, Bioorg. Med. Chem. Lett. 2007,17,527-532.
Embodiment 45B
2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] thiopropionamide
According to the described method of embodiment 1B, with embodiment 45A alternate embodiment 1A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.48-1.85(m,?9?H),?1.87-2.20(m,?8?H),?2.40(s,?2?H),?2.87(s,?3?H),?4.32-4.46(m,?1?H),?6.94-7.13(m,?1?H),?7.14-7.32(m,?1?H),?7.32-7.51(m,?1?H),?9.40(d, J=7.1?Hz,?1?H);?MS(DCI+)?m/ z444(M+H) +。C 21H 27NF 2O 3S 2The analytical calculation value: C, 56.86; H, 6.14; N, 3.16.Measured value: C, 57.61; H, 5.82; N, 3.11.
Embodiment 45C
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine
According to the described method of embodiment 1C, with embodiment 45B alternate embodiment 1B, synthesising title compound. 1H?NMR(500?MHz,?CDCl 3)δ?ppm?1.39-1.77(m,?9?H),?1.86(t, J=14.0?Hz,?2?H),?2.03-2.33(m,?8?H),?2.69-2.86(m,?3?H),?3.95-4.15(m,?1?H),?6.69-6.99(m,?2?H),?7.01-7.16(m,?1?H),?7.42(d, J=7.6?Hz,?1?H);?MS(DCI+)?m/ z452(M+H) +。
Embodiment 46
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-formic acid
Embodiment 46A
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-methyl-formiates
Use embodiment 2 described methods; Handling embodiment 8B and 4-amino bicyclic [2.2.2] octane-1-methyl-formiate (obtains with bicarbonate aqueous solution washing 4-methoxycarbonyl-two ring [2.2.2] suffering-1-ammonium chloride salt; Prime Organics), obtain title compound.LCMS(ESI +)?m/ z404(M+H) +。
Embodiment 46B
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-formic acid
According to the described method of embodiment 14A, with embodiment 46A alternate embodiment 11, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.62(s,?6?H),?1.72-1.88(m,?6?H),?1.90-2.06(m,?6?H),?6.92-7.01(m,?2?H),?7.25(s,?1?H),?7.34-7.42(m,?2?H),?12.09(s,?1?H);?MS(ESI +)?m/ z391(M+H) +。
Another preparation method of embodiment 46
Use embodiment 87 described methods, substitute N-cyanic acid-2-methyl-2-phenoxy third imido acid ethyl ester (CI-1), also can prepare title compound with embodiment 8B.[Waters 2767 with preparation reversed-phase HPLC purifying; Benetnach 10-C18 20 * 250 mm, 10 μ m; 45-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places].
Embodiment 47
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-methane amides
According to the described method of embodiment 14B, with embodiment 46B alternate embodiment 14A, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.62(s,?6?H),?1.69-1.83(m,?6?H),?1.89-2.05(m,?6?H),?6.73(s,?1?H),?6.92-7.01(m,?2?H),?6.95(s,?1?H),?7.24(s,?1?H),?7.33-7.44(m,?2?H);?MS(ESI +)?m/ z390(M+H) +。
The another kind of preparation method of first of embodiment 47
Also use embodiment 85 described methods, substitute 4-(difluoromethyl) two ring [2.2.2] suffering-1-amine (BA-4), preparation embodiment 47 with 4-amino bicyclic [2.2.2] octane-1-methane amide (BA-6).
Second another kind of preparation method of embodiment 47
Embodiment 8B (524 mg, 2 mmol) and 4-amino bicyclic [2.2.2] octane-1-nitrile (BA-1) (300 mg, 2 mmol) are mixed, and in nitrogen atmosphere with purified mixture heating up to 130 ℃, stirred 3 hours.After the cooling, this mixture is dissolved in a spot of ethanol, [Waters 2767 with preparation reversed-phase HPLC purifying; Benetnach 10-C18 20 * 250 mm, 10 μ m; 40-60% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places], obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?11.23(br,?1H),?9.72(s,?1H),?7.22(d, J=8.5Hz,?2H),?6.88(d, J=8.6Hz,?2H),?4.03(s,?2H),?2.00~2.10(m,?12H),?1.50(s,?6H);?LCMS(ESI+)?m/ z389.7(M+H) +。
Embodiment 48 (E)-4-((1E)-2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate
Embodiment 48A
2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-the 2 Methylpropionic acid methyl esters
To (1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptane (Steiner, G.; Deng the people, Heterocycles, 1995,40; 319-330) the N of (1.0 g, 1.3 mmol) adds salt of wormwood (1.0 g in dinethylformamide (40 mL) solution; 7.5 mmol) with the 2 bromo 2 methyl propionic acid methyl esters (0.4 mL, 3.0 mmol, Aldrich).After 80 ℃ are stirred 16 hours down, cool off this reaction mixture, and water (30 mL) cancellation.Extract water layer with ETHYLE ACETATE (3 * 50 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure.Then resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, the 0-50% ethyl acetate/hexane), obtain title compound.MS(ESI +)?m/ z308(M+H) +。
Embodiment 48B
(E)-4-(2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-the 2-methylpropionyl } amino) diamantane-1-methyl-formiate
In the methyl alcohol (4 mL) of embodiment 48A (0.44 g, 1.4 mmol) and water (4 mL) solution, add the 5N NaOH aqueous solution (1.4 mL, 7.1 mmol).After 60 ℃ are down stirred 16 hours, cool off this reaction mixture, be neutralized to pH～7 with 3N HCl, concentrate, acquisition bullion 2-[(1S, 5R, 6S)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-2 Methylpropionic acid.
To the N of above-mentioned acid (1.0 g, 3.4 mmol), add I-hydroxybenzotriazole hydrate (0.6 g in dinethylformamide (25 mL) and THF (25 mL) solution; 3.9 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (0.8 g, 4.1 mmol; Aldrich), (E)-4-aminoadamantan-(Becker, C.L. wait the people to 1-methyl-formiate hydrochloride; Org. Process R & D, 2008,12; 1114-1118) (0.8 g, 3.4 mmol) and triethylamine (0.7 mL, 5.1 mmol).At room temperature stirred this reaction mixture 16 hours, water (30 mL) cancellation then.Extract water layer with methylene dichloride (3 * 50 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure.Then resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, the 0-50% ethyl acetate/hexane), obtain title compound.MS(ESI +)?m/ z485(M+H) +。
Embodiment 48C
(E)-4-(2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-2-methyl sulfo-propionyl group } amino) diamantane-1-methyl-formiate
According to the described method of embodiment 1B, with embodiment 48B alternate embodiment 1A, synthesising title compound.MS(ESI +)?m/ z501(M+H) +。
Embodiment 48D
(E)-4-((1E)-2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate
To embodiment 48C (240 mg; 0.48 add triethyl oxygen
Figure 873310DEST_PATH_IMAGE010
a tetrafluoro borate (1.5 mL in methylene dichloride mmol) (15 mL) solution; 1.5 mmol, 1 M is in methylene dichloride; Aldrich), and with mixture stirred 3 days down at 50 ℃.This reaction mixture of concentrating under reduced pressure then, and in ether, grind.The deposition that obtains is dissolved in ethanol (2 mL) and the cyanamide (60 mg, 1.5 mmol), and adds triethylamine (0.2 mL, 1.5 mmol).After 80 ℃ are stirred 16 hours down, cool off this reaction mixture, concentrating under reduced pressure, and water (10 mL) dilution.Extract water layer with ETHYLE ACETATE (3 * 10 mL).The organic extraction that merges is used anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure.Then resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, the 0-100% ethyl acetate/hexane), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.40(s,?3?H),?1.41(s,?3?H),?1.57-1.69(m,?2?H),?1.77-1.99(m,?10?H),?2.07-2.31(m,?4?H),?2.40-2.49(m,?2?H),?2.68-2.94(m,?4?H),?3.60(s,?3?H),?4.11-4.20(m,?1?H),?7.24-7.30(m,?2?H),?7.33-7.40(m,?2?H),?8.84(d, J=8.1?Hz,?1?H);?MS(ESI +)?m/ z510(M+H) +。
Embodiment 49
(1E)-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-2-phenoxy third amidine
In inert atmosphere, in methyl alcohol (2 mL) solution of embodiment 8 (50 mg, 0.13 mmol), add ammonium formiate (81 mg, 1.3 mmol) and 10% Pd/C (2 mg).This reaction mixture was at room temperature stirred 2 hours, filter concentrating under reduced pressure.(, title compound is provided with resistates with preparation HPLC purifying Phenomenex Luna C8 (2) 5 μ m 100 AXIA posts (on the 30mm * 75mm), use the gradient of 20% to 95% acetonitrile/10 mM ammonium acetates, through 10 minutes, flow velocity 50 mL/ minutes). 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.34-1.47(m,?2?H),?1.55-1.78(m,?9?H),?1.64(s,?6?H),?1.94-2.02(m,?1?H),?2.13-2.25(m,?2?H),?3.89-4.05(m,?1?H),?6.98(d, J=8.7?Hz,?2?H),?7.12(t, J=7.3?Hz,?1?H),?7.27-7.41(m,?2?H),?7.59(d, J=6.7?Hz,?1?H);?MS(ESI +)?m/ z354(M+H) +。
Embodiment 50
(E)-4-{ [(1E)-and N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } diamantane-1-methane amide
According to embodiment 49 described methods, with embodiment 14B alternate embodiment 8, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.45-1.56(m,?2?H),?1.65(s,?6?H),?1.67-1.78(m,?4?H),?1.79-1.94(m,?5?H),?2.10-2.19(m,?2?H),?3.97-4.09(m,?1?H),?6.73(s,?1?H),?6.95-7.04(m,?3?H),?7.08-7.17(m,?1?H),?7.29-7.40(m,?2?H),?7.65(d, J=6.8?Hz,?1?H);?MS(ESI +)?m/ z381(M+H) +。
Embodiment 51
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine
Embodiment 51A
2-(2,4 difluorobenzene oxygen base)-2-methyl propanamide
To 2-(2,4 difluorobenzene oxygen base)-2 Methylpropionic acid (10.0 g, 46.3 mmol; Chembridge) add I-hydroxybenzotriazole hydrate (8.5 g in methylene dichloride (200 mL) solution; 55.5 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (10.6 g, 55.5 mmol; Aldrich) and volatile caustic (54.0 g, 463 mmol).At room temperature stirred this reaction mixture 16 hours, water (100 mL) cancellation then.Extract water layer with methylene dichloride (3 * 100 mL).With the organic extraction that salt solution, 5% Citric Acid and salt solution (100 mL separately) washing merges, use anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure obtains title compound.MS(ESI +)?m/ z233(M+NH 4) +。
Embodiment 51B
2-(2,4 difluorobenzene oxygen base)-2-methyl propionitrile
At 0 ℃, in the methylene dichloride (10 mL) of embodiment 51A (0.9 g, 4.0 mmol) and triethylamine (2.2 mL, 15.8 mmol) solution, add 2,2,2-trifluoroacetic anhydride (1.6 mL, 11.9 mmol).This reaction mixture is warming up to room temperature, stirred three hours, then add methyl alcohol, the quencher reaction.Use saturated NaHCO 3This reaction mixture of solution washing is used anhydrous Na 2SO 4Drying is filtered concentrating under reduced pressure.Resistates is used purified, use Analogix Intelliflash 280 TM(SiO 2, 0-100% methanol/ethyl acetate (1/10) is in hexane), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.71(s,?6?H),?7.08-7.18(m,?1?H),?7.36-7.49(m,?2?H)。
Embodiment 51C
2-(2,4 difluorobenzene oxygen base)-2-methyl-prop imido acid carbethoxy hydrochloride
Under 0 ℃, in methylene dichloride (10 mL) cooling solution of embodiment 51B (6.5 g, 33 mmol) and ethanol (9.6 mL, 165 mmol), blasted HCl gas 30 minutes.With this reaction remain in the refrigerator, following 60 hours at 4 ℃.Concentrate this reaction mixture then, and grind, obtain the deposition of title compound with diethyl ether.MS(ESI +)?m/ z244(M+H) +。
Embodiment 51D
N-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop imido acid ethyl ester
Use the described method of embodiment 3B, handle embodiment 51C and cyanamide (Aldrich), obtain title compound.MS(ESI +)?m/ z286(M+NH 4) +。
Embodiment 51E
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 51D alternate embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?.39-1.50(m,?2?H),?1.62(s,?6?H),?1.62-1.80(m,?8?H),?1.99-2.10(m,?1?H),?2.14-2.25(m,?2?H),?3.93-4.04(m,?1?H),?4.50(s,?1?H),?7.01-7.18(m,?1?H),?7.25-7.49(m,?2?H),?7.82(d, J=6.4?Hz,?1?H);?MS(ESI +)?m/ z390(M+H) +。
Embodiment 52
(1E)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine
According to the described method of embodiment 3C; Use E-4-amino-diamantane-1-nitrile (International Publication specification sheets WO 2007/118185 respectively; Applied on October 18th, 2007) and the alternative E-2-amino of embodiment 51D-5-hydroxyadamantane and embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.52-1.69(m,?2?H),?1.63(s,?6?H),?1.72-1.83(m,?2?H),?1.87-2.25(m,?8?H),?2.42-2.61(m,?1?H),?3.99-4.15(m,?1?H),?7.02-7.15(m,?1?H),?7.23-7.35(m,?1?H),?7.35-7.46(m,?1?H),?7.88(d, J=6.7?Hz,?1?H);?MS(ESI +)?m/ z390(M+H) +。
Embodiment 53
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-methyl-prop amidine
Embodiment 53A
2-(4-chloro-2-fluorophenoxy)-2 Methylpropionic acid ethyl ester
4-chloro-2-fluorophenol (11.280g, 77 mmol), 2-isobutyl ethyl bromide (12.61 mL, 85 mmol) and cesium carbonate (37.6 g, 115 mmol) at N, the mixture in the dinethylformamide (100 mL), were stirred 18 hours down at 55 ℃.Reaction mixture is poured in the salt solution, and extracted with ETHYLE ACETATE (2 * 250 mL).With the organic phase that brine wash merges, dry (MgSO 4), concentrate.Bullion just can be used for next step without additional purification.MS(DCI+)?m/ z278(M+NH 4) +。
Embodiment 53B
2-(4-chloro-2-fluorophenoxy)-2 Methylpropionic acid
Embodiment 53A (18 g, 70 mmol) is handled with LiOH (4.96 g, 207 mmol) in the mixture of THF (100 mL) and water (50 mL).Stir this reaction mixture at 55 ℃ and spend the night, then concentrating under reduced pressure is removed THF.(2 * 100 mL) extracts alkaline water layer with ETHYLE ACETATE, extracts unreacted initial phenol.Water layer is acidified to pH～3, extracts with ETHYLE ACETATE (2 * 200 mL).With the organic layer that brine wash merges, dry (MgSO 4), concentrate.Bullion just can be used for next step without additional purification.MS(DCI+)?m/ z233(M+H) +。
Embodiment 53C
2-(4-chloro-2-fluorophenoxy)-2-methyl propanamide
In methylene dichloride (200 mL) solution of embodiment 53B (14.6 g, 62.8 mmol), add N 1-((ethyl imino-) methylene radical)-N 3, N 3-dimethylpropane-1,3-diamine hydrochloride (8.50 g, 55.5 mmol), and with reaction mixture stirring 1 hour.Add volatile caustic (87 mL, 628 mmol).At room temperature stirred this reaction mixture 16 hours, water (100 mL) cancellation then.Extract water layer with methylene dichloride (3 * 100 mL).Use saturated NaHCO 3, the organic layer that merges of salt solution (100 mL) washing, dry (MgSO 4), filter, concentrate.Resistates is ground with hexane/ethyl acetate (95/5), title compound is provided.MS(DCI+)?m/ z232(M+H) +。
Embodiment 53D
2-(4-chloro-2-fluorophenoxy)-2-methyl propionitrile
At 0 ℃, in the methylene dichloride (100 mL) of embodiment 53C (8 g, 34.5 mmol) and triethylamine (19.25 mL, 138 mmol) solution, add trifluoroacetic anhydride (slowly adding 14.63 mL, 104 mmol).After the adding, solution is warming up to room temperature, and stirred 2 hours, then add methyl alcohol (20 mL), the quencher reaction.Use saturated NaHCO 3This solution of solution washing, dry (Na 2SO 4), concentrate.Use the purified resistates, use Analogix Intelliflash 280 TM(SiO 2, the 0-60% ethyl acetate/hexane), title product is provided.MS(DCI+)?m/ z214(M+H) +。
Embodiment 53E
2-(4-chloro-2-fluorophenoxy)-2-methyl-prop imido acid carbethoxy hydrochloride
Under 0 ℃, in the ethanol (75 mL) of embodiment 53D (7.2 g, 33.7 mmol) and methylene dichloride (30 mL) cooling solution, blasted HCl gas 30 minutes.This reaction is remained on 24-72 hour (utilizing LCMS to detect) in the refrigerator.Concentrate this reaction mixture then, and resistates is ground with diethyl ether.Filter and collect title compound.
Embodiment 53F
2-(4-chloro-2-fluorophenoxy)-N-cyanic acid-2-methyl-prop imido acid ethyl ester
With embodiment 53E (9.9 g; 33.4 acetonitrile mmol) (15 mL) solution joins in water (70 mL) solution of single phosphoric acid hydrogen list sodium hydrate (18.32 g, 134 mmol) and sodium hydrogen phosphate heptahydrate (17.92 g, 66.9 mmol); Then add cyanamide (2.81 g, 66.9 mmol).At room temperature stir this reaction mixture 55 hours, and then used methylene dichloride (3 * 50 mL) to extract.Dry (Na 2SO 4) organic extraction that merges, filter, concentrate, obtain title compound.MS(DCI+)?m/ z302(M+NH 4) +。
Embodiment 53G
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, E-4-aminoadamantan-1-nitrile (International Publication WO applied on October 18th, 2007/118185,2007) substitutes E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.47-1.84(m,?9?H),?1.85-2.29(m,?10?H),?4.02-4.17(m,?1?H),?7.12-7.35(m,?2?H),?7.47-7.66(m,?1?H),?7.85(d, J=6.8?Hz,?1?H);?MS(DCI+)?m/ z415(M+H) +。C 22H 24N 4The analytical calculation value of ClFO: C, 63.69; H, 5.83; N, 13.50.Measured value: C, 63.50; H, 5.89; N, 13.32.
Embodiment 54
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, (E)-4-aminoadamantan-1-sulphonamide (Sorensen, B.; Deng the people, Bioorg. Med. Chem. Lett., 2007; 17,527-532) substitute E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.45-1.72(m,?8?H),?1.73-2.14(m,?10?H),?2.27(s,?2?H),?6.63(s,?2?H),?7.17-7.37(m,?2?H),?7.49-7.68(m,?1?H),?7.89(d, J=6.7?Hz,?1?H);?MS(DCI+)?m/ z469(M+H) +。C 21H 26N 4ClFO 3The analytical calculation value of S: C, 63.69; H, 5.83; N, 13.50.Measured value: C, 53.18; H, 5.95; N, 10.28.
Embodiment 55
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.43(d, J=13.2?Hz,?2?H),?1.56-1.81(m,?14?H),?1.93-2.07(m,?1?H),?2.19(s,?2?H),?4.01(d, J=7.1?Hz,?1?H),?4.50(s,?1?H),?7.19-7.37(m,?2?H),?7.48-7.67(m,?1?H),?7.79(d, J=6.8?Hz,?1?H);?MS(DCI+)?m/ z406(M+H) +。C 21H 25N 3ClFO 20.25H 2The analytical calculation value of O: C, 61.46; H, 6.26; N, 10.24.Measured value: C, 61.76; H, 6.26; N, 10.17.
Embodiment 56
N-[(outward)-two ring [2.2.1] heptan-2-yl]-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine
According to the described method of embodiment 3C, substitute E-2-amino-5-hydroxyadamantane and embodiment 3B, synthesising title compound respectively with amino norbornane (Aldrich) of outer-2-and embodiment 51D. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.00-1.25(m,?4?H),?1.37,?1.38(s,?3?H),?1.40-1.55(m,?4?H),?1.56,?1.58(s,?3?H),?1.61-1.67(m,?1?H),?2.08-2.31(m,?2?H),?3.51-3.60,?3.70-3.80(m,?1?H),?6.98-7.21(m,?2?H),?7.25-7.41(m,?2?H),?7.66,?8.27(d, J=6.4?Hz,?d, J=6.8?Hz,?1?H);?MS(ESI +)?m/ z334(M+H) +。
Embodiment 57
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine
Use the described method of embodiment 3C, handle embodiment 51D with (E)-4-aminoadamantan-1-sulphonamide (Sorensen, people such as B., Bioorg. Med. Chem. Lett., 2007,17,527-532), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.48-1.57(m,?2?H),?1.63(s,?6?H),?1.74-2.11(m,?9?H),?2.22-2.32(m,?2?H),?3.96-4.06(m,?1?H),?6.64(s,?2?H),?7.08(t, J=7.8?Hz,?1?H),?7.27-7.35(m,?1?H),?7.38-7.45(m,?1?H),?7.92(d, J=6.1?Hz,?1?H);?MS(ESI +)?m/ z456(M+H) +。
Embodiment 58
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine
Embodiment 58A
2-(5-chloro-pyridine-2-base oxygen base)-2-methyl propanamide
According to the described method of embodiment 51A, substitute 2-(2,4 difluorobenzene oxygen base)-2 Methylpropionic acid, synthesising title compound with 2-(5-chloro-pyridine-2-base oxygen base)-2 Methylpropionic acid.(Liu, P. wait the people, Journal of Medicinal Chemistry, and 2007,50,15,3427-3430).MS(ESI +)?m/ z215(M+H) +。
Embodiment 58B
2-(5-chloro-pyridine-2-base oxygen base)-2-methyl propionitrile
According to the described method of embodiment 51B, with embodiment 58A alternate embodiment 51A, synthesising title compound.MS(ESI +)?m/ z197(M+H) +。
Embodiment 58C
2-(5-chloro-pyridine-2-base oxygen base)-2-methyl-prop imido acid carbethoxy hydrochloride
According to the described method of embodiment 51C, with embodiment 58B alternate embodiment 51B, synthesising title compound.MS(ESI +)?m/ z244(M+H) +。
Embodiment 58D
2-(5-chloro-pyridine-2-base oxygen base)-N-cyanic acid-2-methyl-prop imido acid ethyl ester
Use the described method of embodiment 3B, handle embodiment 58C and cyanamide (Aldrich), obtain title compound.MS(ESI +)?m/ z268(M+NH 4) +。
Embodiment 58E
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 58D alternate embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.34-1.47(m,?2?H),?1.56-1.74(m,?7?H),?1.77(s,?6?H),?1.95-2.04(m,?2?H),?2.13-2.21(m,?2?H),?3.79-3.87(m,?1?H),?4.44(s,?1?H),?6.94(d, J=8.8?Hz,?1?H),?7.16(d, J=6.4?Hz,?1?H),?7.85(dd, J=8.8,?2.7?Hz,?1?H),?8.00(d, J=2.4?Hz,?1?H);?MS(ESI +)?m/ z390(M+H) +。
Embodiment 59
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-methyl-prop amidine
According to the described method of embodiment 3C, use E-4-aminoadamantan-1-nitrile (International Publication WO applied on October 18th, 2007/118185,2007) and embodiment 58D to substitute E-2-amino-5-hydroxyadamantane and embodiment 3B, synthesising title compound respectively. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.51-1.64(m,?2?H),?1.78(s,?6?H),?1.80-1.94(m,?3?H),?1.98(d,?2?H),?2.06(d,?4?H),?2.17(d,?2?H),?3.92(d,?1?H),?6.94(d, J=8.7?Hz,?1?H),?7.26(d, J=5.6?Hz,?1?H),?7.86(dd, J=8.7,?2.8?Hz,?1?H),?7.99(d, J=2.8?Hz,?1?H);?MS(ESI +)?m/ z399(M+H) +。
Embodiment 60
(1E)-N-(diamantane-1-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, the 1-amantadine substitutes E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.50-1.92(m,?12?H)2.01-2.17(m,?9?H)7.13-7.33(m,?2?H)7.37(s,?1?H)7.56(dd, J=10.71,?2.38?Hz,?1?H);?MS(DCI+)?m/ z390(M+H) +。
Embodiment 61
2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-encircles octyl group-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, 1-ring octyl amine substitutes E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.30-1.84(m,?20?H),?4.11(d, J=5.6?Hz,?1?H),?7.10(t, J=8.9?Hz,?1?H),?7.19-7.31(m,?1?H),?7.54(dd, J=10.5,?2.6?Hz,?1?H),?8.58(d, J=7.9?Hz,?1?H);?MS(DCI+)?m/ z366(M+H) +。
Embodiment 62
(1E)-N-[(E)-diamantane-2-yl]-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, the 2-amantadine substitutes E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.51-1.94(m,?18?H)2.06(s,?2?H)4.00-4.15(m,?1?H)7.23-7.31(m,?2?H)7.59(dd, J=10.17,?1.70?Hz,?1?H)7.86(d, J=7.12?Hz,?1?H);?MS(DCI+)?m/ z390(M+H) +。C 21H 25ClN 3The analytical calculation value of FO: C, 64.69; H, 6.46; N, 10.78.Measured value: C, 64.33; H, 6.34; N, 9.79.
Embodiment 63
(E)-4-{ [(1E)-and 2-(4-chloro-2-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methyl-formiate
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, (E)-4-aminoadamantan-1-methyl-formiate (Becker, C.L.; Deng the people, Org. Process R & D, 2008; 12,1114-1118) substitute E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.56(d, J=13.22?Hz,?2?H)1.65(s,?6?H)1.71-2.00(m,?10?H)2.17(s,?2?H)3.60(s,?3?H)4.05(dd, J=3.73,?1.36?Hz,?1?H)7.14-7.33(m,?1?H)7.58(dd, J=10.17,?1.70?Hz,?1?H)7.87(d, J=7.12?Hz,?1?H);?MS(DCI+)?m/ z390(M+H) +。C 23H 27N 3FO 3The analytical calculation value: C, 61.67; H, 6.08; N, 9.38.Measured value: C, 61.46; H, 5.89; N, 9.29.
Embodiment 64
(1E)-N'-cyanic acid-2-methyl-N-[(E)-5-(methyl sulphonyl) diamantane-2-yl]-2-phenoxy third amidine
According to embodiment 78 described methods, with embodiment 19 alternate embodiments 53, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.43-1.84(m,?10?H)1.86-2.15(m,?7?H)2.32(s,?2?H)2.85(s,?3?H)4.04(d, J=1.36?Hz,?1?H)6.99(d, J=7.80?Hz,?2?H)7.12(t, J=7.29?Hz,?1?H)7.23-7.43(m,?2?H)7.70(d, J=6.44?Hz,?1?H);?MS(DCI+)?m/ z415(M+H) +。C 22H 24N 4The analytical calculation value of ClFO: C, 63.59; H, 7.03; N, 10.11.Measured value: C, 63.06; H, 7.03; N, 9.97.
Embodiment 65
N'-cyanic acid-N-encircles octyl group-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine
According to the described method of embodiment 3C, substitute E-2-amino-5-hydroxyadamantane and embodiment 3B, synthesising title compound respectively with cyclooctylamine (Aldrich) and embodiment 51D. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.38-1.56(m,?8?H),?1.55-1.61(m,?6?H),?1.62-1.82(m,?6?H),?4.02-4.20(m, J=7.9?Hz,?1?H),?7.01-7.10(m,?1?H),?7.11-7.21(m,?1?H),?7.31-7.42(m, J=23.0?Hz,?1?H),?8.58(d, J=8.3?Hz,?1?H);?MS(ESI +)?m/ z350(M+H) +。
Embodiment 66
N-(outer-two rings [2.2.1] heptan-2-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, outer-two ring [2.2.1] heptyl amices substitute E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?0.99-1.29(m,?3?H)1.35-1.77(m,?11?H)2.09-2.36(m,?2?H)3.61-3.92(m,?1?H)7.10(t, J=8.82?Hz,?1?H)7.18-7.36(m,?1?H)7.53(dd, J=10.68,?2.54?Hz,?1?H)8.27(d, J=6.44?Hz,?1?H);?MS(DCI+)?m/ z349(M+H) +。
Embodiment 67
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine
Use the described method of embodiment 3C, handle embodiment 58D with (E)-4-aminoadamantan-1-sulfone (Sorensen, people such as B., Bioorg. Med. Chem. Lett., 2007,17,527-532), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.47-1.62(m,?2?H),?1.79(s,?6?H),?1.82-2.11(m,?9?H),?2.23-2.38(m,?2?H),?2.84(s,?3?H),?3.84-3.96(m,?1?H),?6.94(d, J=9.5?Hz,?1?H),?7.29(d, J=5.8?Hz,?1?H),?7.86(dd, J=8.8,?2.7?Hz,?1?H),?8.01(d, J=2.4?Hz,?1?H);?MS(ESI +)?m/ z452(M+H) +。
Embodiment 68
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine
Use the described method of embodiment 3C, handle embodiment 58D with (E)-4-aminoadamantan-1-sulphonamide (Sorensen, people such as B., Bioorg. Med. Chem. Lett., 2007,17,527-532), obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.41-1.55(m,?2?H),?1.78(s,?6?H),?1.80-2.09(m,?9?H),?2.21-2.29(m,?2?H),?3.80-3.89(m,?1?H),?6.59(s,?2?H),?6.94(d, J=8.8?Hz,?1?H),?7.29(d, J=6.4?Hz,?1?H),?7.86(dd, J=8.8,?2.7?Hz,?1?H),?8.02(d, J=2.7?Hz,?1?H);?MS(ESI +)?m/ z453(M+H) +。
Embodiment 69
N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-N-(six hydrogen-2,5-first bridge pentalene-3a (1H)-yl)-2-methyl-prop amidine
According to embodiment 38 described methods, with embodiment 51D alternate embodiment 8B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.48-1.59(m, J=11.9?Hz,?4?H),?1.62(s,?6?H),?1.87-2.16(m,?6?H),?2.21-2.30(m,?2?H),?2.60(t, J=6.5?Hz,?1?H),?7.02-7.13(m,?1?H),?7.14-7.26(m,?1?H),?7.32-7.46(m,?1?H),?8.23(s,?1?H);?MS(ESI +)?m/ z360(M+H) +。
Embodiment 70
(E)-4-{ [(1E)-and N-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide
Embodiment 70A
(E)-and 4-{ [(benzyloxy) carbonyl] amino } diamantane-1-methyl-formiate
Benzyl chloroformate (6.9 mL, 48.8 mmol) is dropwise joined (E)-4-aminoadamantan-1-methyl-formiate hydrochloride (Becker, C.L.; Deng the people, Org. Process R & D, 2008; 12; 1114-1118) anhydrous methylene chloride (100 mL) of (10.0 g, 40.7 mmol) and diisopropylethylamine (21.3 mL, 122 mmol) stirs and cools off in (0 ℃) solution.After at room temperature stirring 2 hours, reaction mixture is used saturated NaHCO 3The aqueous solution (50 mL) cancellation.Use 50% NaHSO 4The aqueous solution (50 mL) and saturated NaHCO 3The aqueous solution (50 mL) washing organic phase, dry (Na 2SO 4), and concentrating under reduced pressure.Resistates is ground in hexane, filter, obtain title compound.MS(ESI +)?m/ z344(M+H) +。
Embodiment 70B
(E)-and 4-{ [(benzyloxy) carbonyl] amino } diamantane-1-formic acid
According to the described method of embodiment 14A, with embodiment 70A alternate embodiment 11, synthesising title compound.LCMS(ESI +)?m/ z330(M+H) +。
Embodiment 70C
[(E)-and 5-formamyl diamantane-2-yl] the carboxylamine benzyl ester
According to the described method of embodiment 14B, with embodiment 70B alternate embodiment 11, synthesising title compound.MS(ESI +)?m/ z329(M+H) +。
Embodiment 70D
(E)-4-aminoadamantan-1-methane amide
In methyl alcohol (20 mL) solution of embodiment 70C (1.0 g, 3.0 mmol), add Pd (OH) 2/ C (0.2 g, 0.3 mmol).At H 2In the atmosphere (balloon), at room temperature stirred this reaction mixture 4 hours.This reaction mixture is filtered through diatomaceous pad, and concentrating under reduced pressure provides title compound.MS(ESI +)?m/ z195(M+H) +。
Embodiment 70E
(E)-4-{ [(1E)-and N-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide
Use the described method of embodiment 3C, handle embodiment 51D and embodiment 70D, obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.46-1.58(m,?2?H),?1.64(s,?6?H),?1.70-2.00(m,?9?H),?2.10-2.20(m,?2?H),?3.98-4.10(m,?1?H),?6.75(s,?1?H),?7.02(s,?1?H),?7.04-7.14(m,?1?H),?7.25-7.36(m,?1?H),?7.36-7.49(m,?1?H),?7.89(d, J=7.1?Hz,?1?H);?MS(ESI +)?m/ z417(M+H) +。
Embodiment 71
(1E)-N-(diamantane-1-yl)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine
Use embodiment 38 described methods, handle embodiment 51D and 1-aminoadamantan, obtain title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.62(s,?6?H),?1.63-1.69(m,?6?H),?2.08(s,?9?H),?7.03-7.12(m,?1?H),?7.26(d, J=24.2?Hz,?1?H),?7.35-7.45(m, J=22.6?Hz,?1?H),?7.39-7.42(m,?1?H);?MS(ESI +)?m/ z375(M+H) +。
Embodiment 72
(1E)-N-(1-azabicyclo [2.2.2] oct-3-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, 1-azabicyclo [2.2.2] oct-3-yl amine substitutes E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.14(t, J=7.29?Hz,?2?H)1.35-1.57(m,?2?H)1.55-1.82(m,?9?H)2.11(d, J=2.71?Hz,?1?H)2.76-3.06(m,?3?H)4.04-4.30(m,?1?H)7.15(t, J=8.82?Hz,?1?H)7.22-7.31(m,?1?H)7.56(dd, J=10.68,?2.54?Hz,?1?H)8.67(d, J=6.10?Hz,?1?H);?MS(DCI+)?m/ z364(M+H) +。
Embodiment 73
2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-(six hydrogen-2,5-first bridge pentalene-3a (1H)-yl)-2-methyl-prop amidine
According to the described method of embodiment 3C, with embodiment 53F alternate embodiment 3B, six hydrogen-2,5-first bridge pentalene-3a (1H)-Ji amine substitutes E-5-hydroxyl-2-aminoadamantan, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.43-1.71(m,?10?H)1.83-2.16(m,?6?H)2.25(s,?2?H)2.60(t, J=6.61?Hz,?1?H)7.14(t, J=8.82?Hz,?1?H)7.21-7.36(m,?1?H)7.54(dd, J=10.68,?2.54?Hz,?1?H)8.21(s,?1?H);?MS(DCI+)?m/ z375(M+H) +。C 20H 23N 3The analytical calculation value of ClFO: C, 64.08; H, 5.92; N, 11.21.Measured value: C, 63.17; H, 6.26; N, 10.76.
Embodiment 74
(E)-4-{ [(1E)-and 2-(4-chloro-2-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide
According to embodiment 14 described methods, with embodiment 63 alternate embodiments 11, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.45-1.70(m,?8?H)1.70-1.99(m,?9?H)2.14(s,?2?H)3.88-4.19(m,?1?H)6.74(s,?1?H)7.01(s,?1?H)7.18-7.37(m,?2?H)7.58(dd, J=9.66,?1.86?Hz,?1?H)7.85(d, J=7.12?Hz,?1?H);?MS(DCI+)?m/ z430(M+H) +。
Embodiment 75
(E)-4-((1E)-and 2-[(5-chloro-pyridine-2-yl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide
Use the described method of embodiment 3C, handle embodiment 58D and embodiment 70D, obtain title compound. 1H?NMR(300?MHz,?CDCl 3)δ?ppm?1.62-1.66(m,?4?H),?1.85(s,?6?H),?1.88-1.94(m,?2?H),?1.98-2.05(m,?5?H),?2.15-2.24(m,?2?H),?4.13-4.23(m,?1?H),?5.20(s,?1?H),?5.57(s,?1?H),?6.85(d, J=9.5?Hz,?1?H),?6.84-6.91(m,?1?H),?7.62(dd, J=8.7,?2.4?Hz,?1?H),?8.03(d, J=2.8?Hz,?1?H);?MS(ESI +)?m/ z417(M+H) +。
Embodiment 76
(E)-4-[(2-methyl-2-phenoxy tetrahydroform acyl group) amino] diamantane-1-methane amide
With embodiment 50 described methods, obtain title compound with by-product form. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.30-1.42(m,?2?H),?1.50(s,?6?H),?1.69-1.88(m,?9?H),?1.93-2.13(m,?2?H),?3.44-3.54(m,?1?H),?6.66(s,?1?H),?6.87-6.99(m,?4?H),?7.17-7.27(m,?2?H));?MS(ESI +)?m/ z356(M+H) +。
Embodiment 77
(1E)-N'-cyanic acid-2-methyl-N-[(E)-5-(methyl sulphonyl) diamantane-2-yl]-2-(pyridine-2-base oxygen base) third amidine
According to embodiment 49 described methods, with embodiment 67 alternate embodiments 8, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.45-1.56(m,?2?H),?1.65(s,?6?H),?1.67-1.78(m,?4?H),?1.79-1.94(m,?5?H),?2.10-2.19(m,?2?H),?3.97-4.09(m,?1?H),?6.73(s,?1?H),?6.95-7.04(m,?3?H),?7.08-7.17(m,?1?H),?7.29-7.40(m,?2?H),?7.65(d, J=6.8?Hz,?1?H);?MS(ESI +)?m/ z381(M+H) +。
Embodiment 78
(1E)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-(2-fluorophenoxy)-2-methyl-prop amidine
Methyl alcohol (3ml) solution of embodiment 53 (50 mg, 0.111 mmol) is handled with ammonium formiate (70.1 mg, 1.111 mmol) and palladium-10% palladium/carbon (1.182 mg, 0.011 mmol).At room temperature stirred this reaction mixture 18 hours.Filter this reaction mixture, concentrate.With reversed-phase HPLC method purifying, use Phenomenex Luna C8, the gradient of 5 μ M, 100 AXIA posts (30 mm * 75 mm) and 10-100% acetonitrile and 10 mM ammonium acetate/water provides title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.52-1.83(m,?10?H)1.89-2.26(m,?9?H)4.07(s,?1?H)7.08-7.42(m,?4?H)7.91(d, J=6.35?Hz,?1?H);?MS(DCI+)?m/ z380(M+H) +。
Embodiment 79
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine
According to embodiment 78 described methods, with embodiment 54 alternate embodiments 53, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.45-1.71(m,?8?H)1.72-2.13(m,?9?H)2.27(s,?2?H)4.02(dd, J=4.92,?1.53?Hz,?1?H)6.63(s,?2?H)7.14-7.42(m,?4?H)7.95(d, J=6.44?Hz,?1?H);?MS(DCI+)?m/ z435(M+H) +。
Embodiment 80
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine
According to embodiment 78 described methods, with embodiment 55 alternate embodiments 53, synthesising title compound. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.45(d, J=13.09?Hz,?2?H)1.54-1.78(m,?14?H)1.91-2.29(m,?3?H)3.99(d, J=2.38?Hz,?1?H)4.51(s,?1?H)7.06-7.44(m,?4?H)7.86(d, J=7.14?Hz,?1?H);?MS(DCI+)?m/ z372(M+H) +。
Embodiment 81
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.1] heptane-1-methane amides
To N-cyanic acid-2-methyl-2-phenoxy third imido acid ethyl ester (CI-1) (300 mg; 1.29 mmol) with 4-amino bicyclic [2.2.1] heptane-1-methane amide (BA-7) (217 mg; 1.29mmol) ethanol (3 mL) mixture in add 4-(dimethylamino) pyridine (47 mg, 0.387 mmol).At room temperature stir this mixture 5 hours, and then be heated to 75 ℃, and stirred overnight.After concentrating, [Waters 2767 with preparation reversed-phase HPLC purifying with resistates; Benetnach 10-C18 20 * 250 mm, 10 μ m; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places], obtain title compound. 1H?NMR(400?MHz,?CD 3OD)δ?ppm?7.34(t, J=7.8Hz,?2H),?7.14(t, J=7.4Hz,?1H),?7.0(d, J=8.4Hz, 2H),?2.10~2.15(m,?4H),?2.01~2.03(m,4H),?1.79~1.83(m,2H),?1.72(s,?6H);?LCMS(ESI+)?m/ z341.7(M+H) +。
Embodiment 82
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.2] octane-1-methane amides
Use embodiment 81 described methods, substitute 4-amino bicyclic [2.2.1] heptane-1-methane amide (BA-7), the preparation title compound with 4-amino bicyclic [2.2.2] octane-1-methane amide (BA-6). 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.32(t, J=8.0Hz,?2H),7.17(t, J=7.2Hz,?1H),?7.06(s,?1H),?6.91(d, J=8.0Hz,?2H),?6.20(s,?1H),?5.85(s,?1H),?4.81(br,?1H),?2.05~2.06(m,?6H),?1.92~1.94(m。6H),?1.68(s,?6H);?LCMS(ESI+)?m/ z355.7(M+H) +。
Embodiment 83
N'-cyanic acid-N-(4-cyano-bicyclo [2.2.1] heptan-1-yl)-2-methyl-2-phenoxy third amidine
Use embodiment 84 described methods, with embodiment 81 alternate embodiments 82, the preparation title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.47(s,?1H),?7.34(t, J=7.95Hz,?2H),?7.20(t, J=7.4Hz,?1H),?6.93(d, J=8.9Hz,?2H),?2.26(s,?2H),?2.07~2.16(m,?4H),?1.90~1.99(m,?4H),?1.71(s,?6H);?LCMS(ESI+)?m/ z323.7(M+H) +。
Embodiment 84
N'-cyanic acid-N-(4-cyano-bicyclo [2.2.2] suffering-1-yl)-2-methyl-2-phenoxy third amidine
In the dichloromethane solution of refrigerative embodiment 82 in ice bath (70 mg, 0.2 mmol) and triethylamine (120 mg, 1.2 mmol), dropwise add trifluoroacetic anhydride (125 mg, 0.6 mmol).After add accomplishing, with this mixture stirred overnight at room temperature.Except that after desolvating, [Waters 2767 with preparation reversed-phase HPLC purifying with resistates; Benetnach 10-C18 20 * 250 mm, 10 μ m; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places], obtain title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.33(t, J=7.85Hz,?2H),?7.19(t, J=7.4Hz,?1H),?7.01(s,?1H),?6.91(d, J=7.6Hz,?2H),?2.01~2.08(m,?12H),?1.69(s,?6H);?LCMS(ESI+)?m/ z337.7(M+H) +。
Embodiment 85
2-(4-chlorophenoxy)-N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.2] suffering-1-yls]-2-methyl-prop amidine
With 4-(difluoromethyl) two ring [2.2.2] suffering-1-amine (BA-4) and embodiment 8B mixing, and in nitrogen atmosphere with purified mixture heating up to 100 ℃, stirred 3 hours.After the cooling, this mixture is dissolved in a spot of ethanol, [Waters 2767 with preparation HPLC purifying; Benetnach 10-C18 20 * 250 mm, 10 μ m; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places], obtain title compound. 1H?NMR(400?MHz,?DMSO- d 6)δ?ppm?7.38(dd, J=8.8Hz?2H),?7.29(s,?1H),?6.96(d, J=8.8Hz?2H),?5.71(t, J=56.4Hz?1H),?1.98(m,?6H),?1.62(s,?6H),?1.58(m,?6H);?LCMS(ESI+)?m/ z396.7(M+H) +。
Embodiment 86
N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.2] suffering-1-yls]-2-methyl-2-phenoxy third amidine
Use embodiment 85 described methods, with N-cyanic acid-2-methyl-2-phenoxy third imido acid ethyl ester (CI-1) alternate embodiment 8B, the preparation title compound.[Waters 2767 to accomplish purifying with the preparation reversed-phase HPLC; Benetnach 10-C18 20 * 250 mm, 10 μ m; 58-78% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places]. 1H?NMR(400?MHz,?DMSO- d 6)δ?ppm?7.33(t, J=7.8Hz,?3H),?7.10(t, J=7.2Hz,?1H),?6.94(d, J=7.7Hz,?2H),?5.70(t, J=56.7Hz,?1H),?1.97~2.01(m,?6H),?1.62(s,?6H),?1.56~1.60(m,?6H);?LCMS(ESI+)?m/ z362(M+H) +。
Embodiment 87
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.2] octane-1-formic acid
N-cyanic acid-2-methyl-2-phenoxy third imido acid ethyl ester (CI-1) (1 mmol) and 4-amino bicyclic [2.2.2] octane-1-methyl-formiate (BA-2) (1 mmol) is mixed, and in nitrogen atmosphere with purified mixture heating up to 100 ℃, stirred 5 hours.After the cooling, with this mixture of silica gel chromatography (mobile phase: CH 2Cl 2/ CH 3OH=50/1), obtain impure ester products, it is dissolved in the methyl alcohol (10 mL).The methyl alcohol (40 mL) and water (1 mL) solution that in this solution, add LiOH (10 mg).This mixture backflow is spent the night.Except that after desolvating, resistates is soluble in water, regulate pH=5～6 with HCl (1mol/L), extract with ETHYLE ACETATE (50 mL * 3).The extract that merges is used brine wash, use dried over sodium sulfate, concentrate.[Waters 2767 with preparation reversed-phase HPLC purifying resistates; Benetnach 10-C18 20 * 250 mm, 10 μ m; 35-60% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places], obtain title compound.
Embodiment 88
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.1] heptane-1-methane amides
Use embodiment 85 described methods, substitute 4-(difluoromethyl) two ring [2.2.2] suffering-1-amine (BA-4), preparation title compound with 4-amino bicyclic [2.2.1] heptane-1-methane amide (BA-7).[Waters 2767 to accomplish purifying with the preparation reversed-phase HPLC; Benetnach 10-C18 20 * 250 mm, 10 μ m; 36-60% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/ minutes; Detect at 214 and 254 nm places]. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.36(s,?1H),?7.30(d, J=8.6Hz,?2H),?6.88(d, J=8.7Hz,?2H),?5.58(s,?1H),?5.41(s,?1H),?1.97~2.13(m,?8H),?1.78~1.82(m,?2H),?1.71(s,?6H);?LCMS(ESI+)?m/ z375.1(M+H) +。
Embodiment 89
N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.1] heptan-1-yl]-2-methyl-2-phenoxy third amidine
Use embodiment 85 described methods; Substitute 4-(difluoromethyl) two ring [2.2.2] suffering-1-amine (BA-4) with 4-(difluoromethyl) two ring [2.2.1] heptan-1-amine (BA-5); N-cyanic acid-2-methyl-2-phenoxy third imido acid ethyl ester (CI-1) the alternate embodiment 8B, the preparation title compound. 1H?NMR(400?MHz,?CDCl 3)δ?ppm?7.50(s,?1H),?7.9(t, J=7.9Hz,?2H),?7.19(t, J=7.6Hz,?1H),?6.94(d, J=7.6Hz,?2H),?5.82(t, J=56.4Hz,?1H),?2.0(m,?8H),?1.72(s,?6H),?1.6~2.0(m,?2H);?LCMS(ESI+)?m/ z348.2(M+H) +。
Embodiment 90
2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine
From embodiment 79 syntheticss, isolate title compound with by-product form. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.24-1.40(m,?2?H)1.42-1.56(m,?6?H)1.79-2.18(m,?12?H)3.20-3.64(m,?2?H)6.52(s,?2?H)6.88-7.26(m,?4?H);?MS(DCI+)?m/ z410(M+H) +。
Embodiment 91
2-(2-fluorophenoxy)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine
From embodiment 80 syntheticss, isolate title compound with by-product form. 1H?NMR(300?MHz,?DMSO- d 6)δ?ppm?1.39-1.63(m,?10?H),?1.72(s,?2?H),?1.88(s,?11?H),?6.89-7.15(m,?3?H),?7.14-7.29(m,?1?H)。MS(DCI+)?m/ z347(M+H) +。
Embodiment 92
N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-2-phenoxy third amidine
With embodiment 49 described methods, obtain title compound with by-product form. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.17-1.33(m,?2?H),?1.48(s,?6?H),?1.50-1.80(m,?6?H),?1.81-2.06(m,?6?H),?4.17-4.39(m,?1?H),?6.84-7.00(m,?3?H),?7.14-7.30(m,?2?H);?MS(ESI +)?m/ z329(M+H) +。
Embodiment 93
5-chloro-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-anisole carbonamidine
Embodiment 93A
5-chloro-2-anisole first imido acid carbethoxy hydrochloride
According to the described method of embodiment 51C, with 5-chloro-2-HOMOVERATRONITRILE (Maybridge) alternate embodiment 51B, synthesising title compound.MS(ESI +)?m/ z214(M+H) +。
Embodiment 93B
5-chloro-N-cyanic acid-2-anisole first imido acid ethyl ester
Use the described method of embodiment 3B, handle embodiment 93A and cyanamide (Aldrich), obtain title compound.MS(ESI +)?m/ z239(M+NH 4) +。
Embodiment 93C
5-chloro-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-anisole carbonamidine
According to the described method of embodiment 3C, with embodiment 93B alternate embodiment 3B, synthesising title compound. 1H?NMR(300?MHz,?DMSO -d 6)δ?ppm?1.29-1.40(m,?2?H),?1.58-1.76(m,?6?H),?1.85-2.03(m,?3?H),?2.13-2.21(m,?2?H),?3.81(s,?3?H),?3.90-3.98(m,?1?H),?4.46(s,?1?H),?7.21(d, J=9.1?Hz,?1?H),?7.35(d, J=2.8?Hz,?1?H),?7.55(dd, J=8.9,?2.6?Hz,?1?H),?8.87(d, J=6.7?Hz,?1?H);?MS(ESI +)?m/ z361(M+H) +。
Use knowledge well known by persons skilled in the art, or utilize the described method of the foregoing description, can prepare following compounds.
Embodiment 93
2-(4-chlorophenoxy)-N'-cyanic acid-N-(4-hydroxyl two ring [2.2.2] suffering-1-yls)-2-methyl-prop amidine.
Embodiment 94
N'-cyanic acid-N-(4-hydroxyl two ring [2.2.2] suffering-1-yls)-2-methyl-2-phenoxy third amidine.
Embodiment 95
2-(4-chlorophenoxy)-N'-cyanic acid-N-(4-cyano-bicyclo [2.2.2] suffering-1-yl)-2-methyl-prop amidine.
Embodiment 96
N'-cyanic acid-N-(4-hydroxyl two ring [2.2.1] heptan-1-yl)-2-methyl-2-phenoxy third amidine.
Method above utilizing described in reaction scheme and the embodiment, or utilize method well known to those skilled in the art, preparation the following example:
4-({ 2-[(4-benzyl chloride base) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(methyl sulphonyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(pyridine-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-cyanobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [2-fluoro-4-(trifluoromethyl) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [4-(difluoro-methoxy) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-{ [4-(difluoro-methoxy) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-({ 2-[(4-chloro-2-luorobenzyl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[(4-chloro-2-luorobenzyl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-{ [2-fluoro-4-(trifluoromethyl) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(pyridine-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-[(2-{ [2-bromo-4-(trifluoromethyl) benzyl] oxygen base }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 6-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2, the 3-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(3, the 4-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [2-(benzyloxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(3, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(3-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2, the 6-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2-cyanobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 3-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(4-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[(3-benzyl chloride base) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-ar-isopropyl benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[(4-methyl-benzyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate;
4-{ [2-(1,3-benzodioxole-5-ylmethoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2, the 4-dichloro benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-cyanobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ 2-[(4-tertiary butyl benzyl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(4-methyl-benzyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(6-picoline-2-yl) methoxyl group] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[(6-picoline-2-yl) methoxyl group] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(quinolin-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{ [4-(trifluoromethyl) benzyl] oxygen base } cyclobutyl) methyl] amino } diamantane-1-methyl-formiate;
4-({ N-cyanic acid-2-[(2, the 4-dichloro benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(quinolin-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(4-ar-isopropyl benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(3-methyl-benzyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{ [4-(difluoro-methoxy) benzyl] oxygen base } cyclopropyl) methyl] amino } diamantane-1-formic acid;
4-({ (cyanoimino) [1-(quinoline-8-ylmethoxy) cyclopropyl] methyl } amino) diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{ [4-(difluoro-methoxy) benzyl] oxygen base } cyclopropyl) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [1-(quinoline-8-ylmethoxy) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{ [4-(trifluoromethyl) benzyl] oxygen base } cyclobutyl) methyl] amino } diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{ [4-(trifluoromethyl) benzyl] oxygen base } cyclobutyl) methyl] amino } diamantane-1-methane amide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } ethanamidine;
N'-cyanic acid-2-(2,6-thebaine-4-yl)-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(4-hydroxy piperidine-1-yl) third amidine;
2-azepan-1-base-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
Carboxylamine 4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino]-the 1-adamantane esters;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino]-1-adamantyl acetic ester;
N-{4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino]-the 1-adamantyl } ethanamide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-fluoro-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } ethanamidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-[4-(5-picoline-2-yl) piperazine-1-yl] third amidine;
2-{ [2-(4-chloro-phenyl-) ethyl] amino }-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
2-(4-benzyl piepridine-1-yl)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(6; 7; 9; 10-tetrahydrochysene-8H-[1,3] dioxole is [4,5-g] [3] benzo-aza
Figure 567597DEST_PATH_IMAGE008
-8-yl also) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(4-pyridine-2-base piperazine-1-yl) third amidine;
N'-cyanic acid-2-[4-(4-fluorophenyl) piperazine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-[4-(4-p-methoxy-phenyl) piperazine-1-yl] third amidine;
N'-cyanic acid-2-[4-(5-cyanopyridine-2-yl) piperazine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[4-(2-furoyl) piperazine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-(1,3-dihydro-2H-isoindole-2-yl)-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[4-(trifluoromethyl) phenyl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
2-[3-(4-chlorophenoxy) azetidine-1-yl]-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[4-(2-fluorophenoxy) piperidines-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[3-(2-fluorophenoxy) piperidines-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[3-(3-fluorophenoxy) tetramethyleneimine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[[2-(3, the 4-dichlorophenyl) ethyl] (methyl) amino]-N-(5-hydroxyl-2-adamantyl) third amidine;
2-[[2-(4-chloro-phenyl-)-1-methylethyl] (methyl) amino]-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
2-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
2-[4-(6-chloro-pyridine-3-yl) piperazine-1-yl]-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(3-phenyl azetidine alkane-1-yl) third amidine;
N'-cyanic acid-N-[5-(methylol)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N-methyl adamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N-methoxyl group diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N-hydroxyadamantane-1-methane amide;
N-[5-(aminomethyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-1-{ [4-(trifluoromethyl) benzyl] amino } the Trimetylene carbonamidine;
4-({ N-cyanic acid-2-methyl-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-1-piperidines-1-basic ring propane carbonamidine;
N'-cyanic acid-2-methyl-N-[5-(5-methyl isophthalic acid; 2,4-
Figure 219158DEST_PATH_IMAGE007
diazole-3-yl)-the 2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-2-methyl-N-[5-(2H-tetrazolium-5-yl)-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-[(2-{4-[[(4-chloro-phenyl-) alkylsulfonyl] (cyclopropyl) amino] piperidines-1-yl }-N-cyanic acid tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] third amidine;
4-{ [N-cyanic acid-2-(3-fluoropyrrolidine-1-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3-fluoropyrrolidine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methyl-formiate;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(2-methyl-4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ 2-[4-(5-chloro-pyridine-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) ethyliminum acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] ethyliminum acyl group } amino) diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclopropyl) methyl] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-methane amide;
N'-cyanic acid-2-methyl-N-[5-(4H-1,2,4-triazole-3-yl)-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(2-furyl methyl) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(pyridin-4-yl methyl) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclopropyl) methyl] amino } diamantane-1-methane amide;
4-({ 2-[4-(4-chloro-phenyl-) piperidines-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-Phenylpiperidine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(1; 2; 4,5-tetrahydrochysene-3H-3-benzo-aza
Figure 202157DEST_PATH_IMAGE008
-3-yl) the tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[4-(trifluoromethyl) phenyl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] ethyliminum acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) ethyliminum acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[2-methyl-4-(5-picoline-2-yl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3-fluorine piperidines-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-{2-(trifluoromethyl)-4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(5-fluorine pyridin-3-yl)-1,4-Diazesuberane-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-cyclopropyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclobutyl) methyl] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{5-[3-(trifluoromethyl) phenyl]-1,5-diazacyclo octane-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(3-aminomethyl phenyl)-1,4-Diazesuberane-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ 2-[7-(5-bromo pyrrole fixed-2-yl)-3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ 2-[5-(6-chloro-pyridine-3-yl) hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-yl also]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(3-pyridin-3-yl-3,9-diazabicyclo [4.2.1] ninth of the ten Heavenly Stems-9-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-([(4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } methyl) phenylformic acid;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-cyclopropyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclobutyl) methyl] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(2-methylcyclohexyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[(3-methylcyclohexyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(suberyl oxygen base)-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(cyclohexyl methoxyl group)-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-{ [2-(benzyloxy)-N-cyanic acid ethyliminum acyl group] amino } diamantane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(1,3-thiazoles-5-ylmethyl) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(2-methoxybenzyl) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(3, the 4-dimethoxy-benzyl) diamantane-1-methane amide;
4-({ 2-[9-(6-chloro-pyridine-3-yl)-3,9-diazabicyclo [4.2.1] ninth of the ten Heavenly Stems-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(2-anilino-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2, the 3-dichlorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-phenylpiperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(4-aminomethyl phenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(1,3-benzothiazole-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(3, the 4-dichlorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(3-aminomethyl phenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[2-(trifluoromethyl) phenyl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2,4 difluorobenzene base) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(6-picoline-2-yl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-pyrimidine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[3-(trifluoromethyl) phenyl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[3-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ 2-[4-(3-chloro-phenyl-) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(4-acetylphenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N, N-dimethyladamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclobutyl] (cyanoimino) methyl] amino } diamantane-1-formic acid;
4-{ [(cyanoimino) (1-phenycyclopropyl) methyl] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-phenyl tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(4-methylcyclohexyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-methane amide;
N-{4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } ethanamide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyrimidine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyrazine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(4-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(3-cyanopyridine-2-yl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(6-picoline-3-yl)-1,4-Diazesuberane-1-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[(2-{4-[3-chloro-5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-phenoxy tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [2-(benzyloxy)-N-cyanic acid ethyliminum acyl group] amino } diamantane-1-methane amide;
4-(2-{ [(4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } ethyl) phenylformic acid;
4-{ [N-cyanic acid-2-methyl-2-(2-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [2-(2-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-phenyl tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [(cyanoimino) (1-phenycyclopropyl) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclobutyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
N'-cyanic acid-N-{5-[(methyl sulphonyl) amino]-2-adamantyl }-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [N-cyanic acid-2-(2-methoxyl group phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(4-methoxyl group phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[3-(trifluoromethyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-(1-hydroxyl-1-methylethyl)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [N-cyanic acid-2-methyl-2-(4-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [2-(3-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(tetrahydrochysene-2H-pyrans-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-phenylpiperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3-methoxyl group phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(trifluoromethoxy) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[methyl (phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2, the 4-Dimethoxyphenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(cyclohexyl methoxyl group)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2,3-dicyano phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-(cyano methyl)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-({ N-cyanic acid-2-methyl-2-[4-(4-nitrophenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-prop amidine;
4-({ N-cyanic acid-2-[4-(2,4 dichloro benzene base) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
N-2-adamantyl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-2-adamantyl-N'-cyanic acid-2-methyl-2-phenyl third amidine;
N-2-adamantyl-N'-cyanic acid-1-benzyl ring propane carbonamidine;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } acetate;
4-({ 2-[4-(4-chloro-2-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[4-(trifluoromethyl) pyrimidine-2-base] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ 2-[4-(3-chloro-4-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(4-bromophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(5-chloro-2-p-methoxy-phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-phenyl-) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2-cyano-phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(2-aminomethyl phenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(4-chloro-phenyl-) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
6-[(1-suberyl-4,4-dimethyl--5-oxo-pyrrolidine-3-yl) methoxyl group] cigarette nitrile;
4-({ 2-[4-(3-chloro-pyridine-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(2-{4-[2-chloro-4-(trifluoromethyl) phenyl] piperazine-1-yl }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3-fluoropyrrolidine-1-yl)-2-methyl-prop imines acyl group] amino }-N-(pyridin-3-yl methyl) diamantane-1-methane amide;
4-({ 2-[(4-chloro-phenyl-) sulfenyl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(3-Phenylpiperidine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ 2-[4-(2-chloro-4-aminomethyl phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [2-(3-bromine phenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
1-suberyl-4-{ [(2-fluorophenyl) (methyl) amino] methyl }-3,3-dimethyl pyrrolidine-2-ketone;
4-({ N-cyanic acid-2-[4-(2-fluorophenyl) piperidines-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(2-aminomethyl phenyl) piperidines-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-4-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-([(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } methyl) phenylformic acid;
4-{ [2-({ 1-[(benzyloxy) carbonyl] piperidin-4-yl } methoxyl group)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2-furoyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-4-cyano-phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-4-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
1-suberyl-3,3-dimethyl--4-(phenoxymethyl) pyrrolidin-2-one;
4-{ [[1-(4-chloro-phenyl-) cyclohexyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclopropyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclopentyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [2-(4-chloro-phenyl-)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [(cyanoimino) (1-benzyl ring amyl group) methyl] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(2, the 3-dimethyl phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
Carboxylamine 4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantane esters;
4-[(2-{4-[(4-chloro-phenyl-) alkylsulfonyl] piperazine-1-yl }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-{ [2-(benzyloxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-(4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--2-oxo-pyrrolidine-1-yl) azepan-1-methane amide;
4-({ N-cyanic acid-2-[4-(2,4 difluorobenzene base) piperidines-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
6-{ [1-(5-hydroxyl ring octyl group)-4,4-dimethyl--5-oxo-pyrrolidine-3-yl] methoxyl group } the cigarette nitrile;
4-({ N-cyanic acid-2-[4-(4-cyanic acid-2-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-(2-(cyanoimino)-4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl pyrrolidine-1-yl) diamantane-1-methane amide;
9-(4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--2-oxo-pyrrolidine-1-yl) two ring [3.3.1] nonane-3-methane amides;
N-[4-(amino-sulfonyl) benzyl]-4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-[2-{ [5-(aminocarboxyl)-2-adamantyl] amino }-2-(cyanoimino)-1,1-dimethyl-oxyethyl group] the phenylcarbamic acid tertiary butyl ester;
4-(4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--2-oxo-pyrrolidine-1-yl) two ring [5.1.0] octane-8-ethyl formates;
N-[4-(aminocarboxyl) benzyl]-4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
[(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] glycocoll;
3-([(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } methyl) phenylformic acid;
4-({ (cyanoimino) [1-(3-fluorophenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-{ [[1-(2-chloro-4-fluorophenyl) cyclopentyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-fluorophenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(2-fluorophenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-methylcyclohexyl) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [1-(2,4 dichloro benzene base) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-p-methoxy-phenyl) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-aminomethyl phenyl) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{3-methyl-4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl)-3,5-dimethyl--1H-pyrazol-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl)-3,5-dimethyl--1H-pyrazol-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
6-{ [4,4-dimethyl--1-(4-methyl bicyclic [2.2.2] suffering-1-yl)-5-oxo-pyrrolidine-3-yl] methoxyl group } the cigarette nitrile;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridin-4-yl phenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
6-{ [1-(5-cyanic acid ring octyl group)-4,4-dimethyl--5-oxo-pyrrolidine-3-yl] methoxyl group } the cigarette nitrile;
4-[(N-cyanic acid-2-methyl-2-thiophene-2-base tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-thiene-3-yl-tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[5-(trifluoromethyl) pyridine-2-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] phenyl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ 2-[4-chloro-2-(tetramethyleneimine-1-base alkylsulfonyl) phenoxy]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(methyl sulphonyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-p-methoxy-phenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(3-aminomethyl phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[2-{ [5-(aminocarboxyl)-2-adamantyl] amino }-2-(cyanoimino)-1, the 1-dimethyl ethyl] piperazine-1-formic acid tertiary butyl ester;
N'-cyanic acid-2-(3-fluoropyrrolidine-1-yl)-N-(5-hydroxyl-2-adamantyl) third amidine;
4-({ N-cyanic acid-2-methyl-2-[2-(methyl sulphonyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ 2-[4-(2-bromophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [2-(4-bromophenyl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ 2-[(3-chloro-phenyl-) amino]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-p-methoxy-phenyl) amino]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl)-3,5-dimethyl--1H-pyrazol-1-yl]-2-methyl-prop imines acyl group } amino)-N-(1,3-thiazoles-5-ylmethyl) diamantane-1-methane amide;
4-({ 2-[4-(6-chloropyrimide-4-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(6-chlorine pyridazine-3-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloropyrimide-4-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(2-{4-chloro-2-[(diethylamino) alkylsulfonyl] phenoxy }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
N-[(4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } amino) carbonyl] glycocoll;
4-({ N-cyanic acid-2-[4-(5-cyanopyridine-2-yl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(3-chloro-5-cyanopyridine-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(1,3-thiazoles-2-yl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[(5-bromo pyrrole is decided-the 2-yl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
1-(5-cyanic acid-2-adamantyl)-4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl pyrrolidine-2-subunit cyanamide;
4-({ N-cyanic acid-2-methyl-2-[4-(tetramethyleneimine-1-base alkylsulfonyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) amino]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [4-(dimethylamino) phenyl] amino }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) phenyl] amino } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethyl) phenyl] amino } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl isophthalic acid-(2-methyl-benzyl)-2-oxo-piperidine-3-yl] methyl } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(2-cyano-benzene oxygen)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-(2-(cyanoimino)-3,3-dimethyl--4-{ [4-(1H-1,2,4-triazol-1-yl) phenoxy] methyl } tetramethyleneimine-1-yl) diamantane-1-methane amide;
4-(2-(cyanoimino)-4-{ [4-(1H-imidazoles-1-yl) phenoxy] methyl }-3,3-dimethyl pyrrolidine-1-yl) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2-hydroxy phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-prop amidine;
4-[2-{ [5-(aminocarboxyl)-2-adamantyl] amino }-2-(cyanoimino)-1, the 1-dimethyl ethyl]-N-(tertiary butyl) piperazine-1-methane amide;
4-{ [N-cyanic acid-2-(4-hydroxyphenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) sulfenyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-(formamido group)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [(1-benzyl-3-methyl-2-oxo-pyrrolidine-3-yl) (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl isophthalic acid-(2-methyl-benzyl)-2-oxo-pyrrolidine-3-yl] methyl } amino) diamantane-1-methane amide;
4-{ [[1-(2-benzyl chloride base)-3-methyl-2-oxo-pyrrolidine-3-yl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(3-benzyl chloride base)-3-methyl-2-oxo-pyrrolidine-3-yl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(2H-tetrazolium-5-yl)-2-adamantyl] third amidine;
4-({ N-cyanic acid-2-methyl-2-[4-(1-methyl isophthalic acid H-pyrazoles-4-yl) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methylthio group)-2-adamantyl] third amidine;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methylsulfinyl)-2-adamantyl] third amidine;
4-{ [2-(3-bromophenyl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(3,5-dimethyl-different azoles-4-yl) phenyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridin-3-yl phenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [({ 4-[(N-cyanic acid-2-methyl-2-thiophene-2-base tetrahydroform acyl group) amino]-1-adamantyl } carbonyl) amino] methyl } phenylformic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(1H-pyrazoles-4-yl) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N-(4-{ [(methyl sulphonyl) amino] carbonyl } benzyl) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) sulfinyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) alkylsulfonyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl isophthalic acid-(1-methyl isophthalic acid-styroyl)-2-oxo-pyrrolidine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(1-styroyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
2-(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) ethanamide;
4-{ [N-cyanic acid-2-methyl-2-(1,3-thiazoles-2-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [[1-(4-benzyl chloride base)-3-methyl piperidine-3-yl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(4-hydroxy phenyl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl]-N'-hydroxyadamantane-1-carbonamidine;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl] diamantane-1-methane amide;
4-{ [(1-benzyl-3-methyl-2-oxo-piperidine-3-yl) (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-Phenoxyphenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) acetate;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl] diamantane-1-carbonamidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(2H-tetrazolium-5-ylmethyl)-2-adamantyl] third amidine;
4-{ [2-(1-thionaphthene-3-yl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
N-{5-[(amino-sulfonyl) methyl]-2-adamantyl }-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [[1-(4-chlorophenoxy) cyclobutyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N'-hydroxyadamantane-1-carbonamidine;
4-[([(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) methyl] alkylsulfonyl } amino) methyl] phenylformic acid;
2-(4-chlorophenoxy)-N'-cyanic acid-N-[5-(1H-imidazoles-2-yl)-2-adamantyl]-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-(5-fluorine pyridine-2-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
3-(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) vinylformic acid;
4-[(N-cyanic acid-2-methyl-2-{ [5-(1H-pyrazol-1-yl) pyridine-2-yl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(5-different
Figure 146160DEST_PATH_IMAGE007
azoles-5-base-2-adamantyl)-2-methyl-prop amidine;
4-[(N-cyanic acid-2-methyl-2-quinoxaline-2-base tetrahydroform acyl group) amino] diamantane-1-methane amide;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-{5-[(2-morpholine-4-base oxethyl) methyl]-2-adamantyl } third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-(2-methylphenoxy) third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-(4-methylphenoxy) third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-[2-(trifluoromethyl) phenoxy] third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-[2-(trifluoromethoxy) phenoxy] third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N'-cyanic acid-N-[5-(1-hydroxyethyl)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
2-{4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } propionic acid;
4-[(N-cyanic acid-3-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-methane amide;
(2R)-and N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the fourth amidine;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-formic acid;
4-[((2R)-N-cyanic acid-3-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-formic acid;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N, N-dimethyladamantane-1-methane amide;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino]-N, N-dimethyladamantane-1-methane amide;
N-{4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino]-the 1-adamantyl } ethanamide;
N-{4-[((2R)-N-cyanic acid-3-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino]-the 1-adamantyl } ethanamide;
N'-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-N-[5-hydroxyl-2-adamantyl] third amidine;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-[(3S)-and 3-(trifluoromethyl) tetramethyleneimine-1-yl] ethanamidine;
4-(N-cyanic acid-2-[(3R)-and 3-fluorine piperidines-1-yl] the tetrahydroform acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-methoxyl group-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } penta imines acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(thiophenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[methyl (phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(2-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(3-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[methyl (phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ 2-[(4-chloro-phenyl-) amino]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [2-(2-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) fourth imines acyl group] amino } diamantane-1-methane amide;
4-[3-benzyl-2-(cyanoimino) tetramethyleneimine-1-yl] diamantane-1-methane amide;
4-({ 2-[4-(2-chloro-4-cyano-phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-methyl-2-phenyl third amidine;
2-(4-chloro-phenyl-)-N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-methyl-prop amidine;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-1-benzyl ring propane carbonamidine;
4-{ [2-(4-bromo-3,5-dimethyl--1H-pyrazol-1-yl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-(2-(cyanoimino)-4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl pyrrolidine-1-yl) diamantane-1-methane amide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N-methyl adamantane-1-methane amide;
4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4'-(methyl sulphonyl)-1,1'-biphenyl-4-yl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3-cyanopyridine-2-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[2-(trifluoromethoxy) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(trifluoromethyl) pyridine-2-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ 2-[(5-bromo pyrrole is decided-the 2-yl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[2-(trifluoromethyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-(2-(cyanoimino)-3,3-dimethyl--4-{ [4-(1H-1,2,4-triazol-1-yl) phenoxy] methyl } tetramethyleneimine-1-yl) diamantane-1-methane amide;
4-{ [(cyanoimino) (2-aminomethyl phenyl) methyl] amino } diamantane-1-methane amide;
4-{ [2-(3-bromo-4-methoxyl group phenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [2-(2-bromo-4-methoxyl group phenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(pyridine-2-ylmethyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(pyridin-3-yl methyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(pyridin-4-yl methyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(2-pyridine-2-base ethyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-3-(4-p-methoxy-phenyl)-2,2-dimethyl--3-oxo tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) phenyl] amino } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) phenyl] sulfenyl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl] diamantane-1-methane amide;
4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N, N-dimethyladamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(1-pyridine-2-base ethyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[3-(1,3-thiazoles-4-ylmethoxy) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[3-(2-morpholine-4-base oxethyl) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
N-[5-(5-amino-4H-1,2,4-triazole-3-yl)-2-adamantyl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-(6-fluorine pyridin-3-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
2-(4-chlorophenoxy)-N'-cyanic acid-N-[5-(methylol)-2-adamantyl]-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-methyl-2-(6-morpholine-4-yl pyridines-3-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(5-fluorine pyridine-2-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[6-(methylamino) pyridin-3-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [5-(1H-imidazoles-1-yl) pyridine-2-yl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [5-(1H-pyrazol-1-yl) pyridine-2-yl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-quinoxaline-2-base tetrahydroform acyl group) amino] diamantane-1-methane amide;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(3-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-(3-methylphenoxy) third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2-methoxyl group phenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(3-methoxyl group phenoxy)-2-methyl-prop amidine;
(2S)-amino (4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) acetate;
2-[(4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) alkylsulfonyl] ethanamide;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-methyl-2-(4-nitrophenyl) third amidine;
N'-cyanic acid-N-[5-(methyl sulphonyl)-2-adamantyl]-1-benzyl ring propane carbonamidine;
2-[(4-pyridine bromide-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
(2S)-2-(4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) propionic acid;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(1,1'-biphenyl-2-base oxygen base)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [2-(1,1'-biphenyl-2-base oxygen base)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
N'-cyanic acid-2-(2,4 dichloro benzene oxygen base)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(2-bromo-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-2-(2-methylphenoxy)-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-2-(4-methylphenoxy)-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(2-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(4-methoxyl group phenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-cyano-benzene oxygen)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-methoxyl group phenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-[(3-pyridine bromide-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-bromo-4-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-3-methyl-2-oxo-1-pyridine-2-base tetramethyleneimine-3-carbonamidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-{5-[(methylthio group) methyl]-2-adamantyl } third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,4 dichloro benzene oxygen base)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2, the 4-dimethyl phenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(4-fluoro-2-methylphenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,6-two chloro-4-methylphenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,6-two chloro-4-fluorophenoxies)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-chloro-4-methylphenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(mesityloxy)-2-methyl-prop amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-{5-[(methyl sulphonyl) methyl]-2-adamantyl } third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(4-fluorophenoxy)-2-methyl-prop amidine;
N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-sec.-propyl phenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(4-fluoro-2-methylphenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl]-2-[2-(trifluoromethyl) phenoxy] third amidine;
4-{ [(cyanoimino) (3-methyl-2-oxo-1-pyridine-2-base tetramethyleneimine-3-yl) methyl] amino } diamantane-1-methane amide;
(2S)-2-amino-2-(4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) ethanamide;
N'-cyanic acid-2-[4-fluoro-2-(1H-pyrazol-1-yl) phenoxy]-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2,6-two chloro-4-fluorophenoxies)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-[4-fluoro-2-(1H-pyrazoles-4-yl) phenoxy]-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl]-2-[3-(trifluoromethoxy) phenoxy] third amidine;
3-deuterium generation-4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino]-7-deuterium generation-diamantane-1-methane amide;
N-[1-deuterium generation-4-adamantyl]-N'-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third amidine;
3-deuterium generation-4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-7-deuterium generation-diamantane-1-methane amide;
N-[1-deuterium generation-4-adamantyl]-N'-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
3-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
N-1-azabicyclo [2.2.2] oct-3-yl-N'-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third amidine;
N-[1-aza-tricycle [3.3.1.13,7] last of the ten Heavenly stems-4-yl]-N'-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-cyclohexyl-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
{ 4-[(4-aminomethyl phenyl) alkylsulfonyl] piperazine-1-yl } (4-nitrophenyl) methylene radical cyanamide;
N'-cyanic acid-N-{1-[(1-cyanic acid cyclopropyl) methyl] piperidin-4-yl }-N-cyclopropyl-4-(2,2,2-three fluoro-1-hydroxyl-1-methylethyls) benzenyl amidine;
Carboxylamine [4-[{ (cyanoimino) [4-(2,2,2-three fluoro-1-hydroxyl-1-methylethyls) phenyl] methyl } (cyclopropyl) amino]-1-(4-fluorophenyl) cyclohexyl] methyl ester;
N'-cyanic acid-N-cyclopropyl-N-[4-(2-hydroxyethyl) cyclohexyl]-4-isopropyl benzene carbonamidine; [5-(4-aminomethyl phenyl) different
Figure 234201DEST_PATH_IMAGE007
azoles-4-yl] (3-pyridin-3-yl tetramethyleneimine-1-yl) methylene radical cyanamide;
4-[4-[(the 1-adamantyl is amino) (cyanoimino) methyl]-5-(1-methyl cyclopropyl)-1H-pyrazol-1-yl] phenylformic acid;
N'-cyanic acid-N-cyclohexyl-2-[(2-styroyl) sulfenyl] pyridine-3-carbonamidine;
4-[5-[(the 2-adamantyl is amino) (cyanoimino) methyl]-6-(rosickyite base) pyridine-2-yl] morpholine-2-formic acid;
N'-cyanic acid-N-cyclopropyl-N-(4-cyclopropyl-4-hydroxy-cyclohexyl)-4-(2,2,2-three fluoro-1-hydroxyl-1-methylethyls) benzenyl amidine;
2-[2-(4-fluorophenyl)-6-hydroxyl-2-adamantyl]-1-(3-hydroxy azetidine-1-yl) ethylidene cyanamide;
2-{1-[2-(the 2-adamantyl is amino)-2-(cyanoimino) ethyl] cyclopentyl }-N-isobutyl-ethanamide;
2-{4-[(2-fluorophenyl) alkylsulfonyl]-1,4-Diazesuberane-1-yl }-1-octahydro quinoline-1 (2H)-Ji ethylidene cyanamide;
1-cyclohexyl-3-[(3,5-two chloro-4'-{ [4-(2-fluoro ethyl) piperazine-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl] tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-piperidines-1-base tetramethyleneimine-2-subunit cyanamide;
3-cyclohexyl-1-[(3,5-two chloro-4'-{ [4-(2-fluoro ethyl) piperazine-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl] tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-(4,4-difluoro cyclohexyl) tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-fluoro-1,1'-biphenyl-4-yl) methyl]-1-(4,4-difluoro cyclohexyl) tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-(4-hydroxy piperidine-1-yl) tetramethyleneimine-2-subunit cyanamide;
4-{2-(cyanoimino)-3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl] tetramethyleneimine-1-yl } piperidines-1-methyl-formiate;
2-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-2-azaspiro [4.5] last of the ten Heavenly stems-1-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-(4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline-6-yl) tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-fluoro-1,1'-biphenyl-4-yl) methyl]-1-(4,5,6,7-tetrahydrochysene-2H-indazole-5-yl) tetramethyleneimine-2-subunit cyanamide;
N-2-adamantyl-2'-the tertiary butyl-N'-cyanic acid-2'H-1,3'-two pyrazoles-4'-carbonamidine;
2-(4-bromo-2-fluorophenyl)-2-hydroxyl-1-(3-oxo-1'H, 3H-spiral shell [2-cumarone-1,3'-tetramethyleneimine]-1'-yl) ethylidene cyanamide;
N'-cyanic acid-N-(1-{ [4-(2, the 5-3,5-dimethylphenyl) piperazine-1-yl] carbonyl } piperidines-3-yl)-4-hydroxyadamantane-1-carbonamidine;
1-{3-[1-(4-chloro-phenyl-) cyclopropyl]-1-oxa--2,7-diaza spiro [4.4] ninth of the ten Heavenly Stems-2-alkene-7-yl } the ethylidene cyanamide;
7-(2-chloro-phenyl-)-1-isobutyl--1,7-diaza spiro [4.4] ninth of the ten Heavenly Stems-6-subunit cyanamide;
8-(3-chloro-pyridine-2-yl)-2-cyclohexyl-2,8-diaza spiro [4.5] last of the ten Heavenly stems-1-subunit cyanamide;
5-{4-[1-(cyanoimino)-2-(4-hydroxy-cyclohexyl)-2,7-diaza spiro [4.5] last of the ten Heavenly stems-7-yl]-3-fluorophenyl }-N, N-lutidine-2-methane amide;
2-(2-acetylphenyl)-N'-cyanic acid-N-encircles octyl group-1,3-thiazoles-4-carbonamidine;
(5-cyclopropyl-1-piperidin-4-yl-1H-pyrazoles-4-yl) { 3-[2-(trifluoromethyl) phenyl] tetramethyleneimine-1-yl } methylene radical cyanamide;
2-[4-(2-{ [(4-chloro-phenyl-) (cyanoimino) methyl] amino } ethyl) phenoxy]-2 Methylpropionic acid;
1'-{ [2-(trifluoromethyl) phenoxy] ethanoyl } spiral shell [indoles-3,4'-piperidines]-2 (1H)-subunit cyanamides;
1-{4-[(the 2-adamantyl is amino) (cyanoimino) methyl] phenyl } piperidines-4-formic acid;
N-(1-{4-[3-azabicyclo [3.2.2] ninth of the ten Heavenly Stems-3-base (cyanoimino) methyl] phenyl } tetramethyleneimine-3-yl)-N-methyl isophthalic acid-phenyl methanesulfonamide acid amides;
1-adamantyl { 4-[2-(1H-imidazoles-2-base sulfenyl) ethyl] piperidines-1-yl } methylene radical cyanamide;
N-2-adamantyl-N'-cyanic acid-4-(2-oxa--5-azabicyclo [2.2.1] heptan-5-yl) benzenyl amidine;
N-{4-[(cyanoimino) (1,3,3-trimethylammonium-6-azabicyclo [3.2.1] suffering-6-yl) methyl] benzyl }-1,1,1-three fluoro-N-sec.-propyl Toluidrins;
1-ethanoyl-N-(2-{5-[(cyanoimino) (1,3,3-trimethylammonium-6-azabicyclo [3.2.1] suffering-6-yl) methyl]-1H-benzoglyoxaline-1-yl } ethyl) piperidines-4-methane amide;
3-{4-[(cyanoimino) (1,3,3-trimethylammonium-6-azabicyclo [3.2.1] suffering-6-yl) methyl]-1H-indoles-1-yl } ethyl propionate;
N-1-adamantyl-N'-cyanic acid-1-(thiophene-2-base alkylsulfonyl) piperidines-4-carbonamidine;
N'-cyanic acid-4-(2,4 dichloro benzene oxygen base)-N-[4-(methylol)-2-adamantyl] fourth amidine;
4-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[4-(methylol) cyclohexyl]-N-methylbenzene carbonamidine;
N-2-adamantyl-N'-cyanic acid-2-[cyclohexyl (methyl) amino] ethanamidine;
N-2-adamantyl-N'-cyanic acid-1-methyl-5-(2-phenyl ethoxy)-1H-pyrazoles-4-carbonamidine;
2,4-two chloro-N-[1-([5-{ (cyanoimino) [(5-hydroxyl-2-adamantyl) amino] methyl }-4-(cyclopentyl sulfenyl) different
Figure 438918DEST_PATH_IMAGE007
azoles-3-yl] the oxygen base } methyl) cyclopropyl] BM;
Carboxylamine 4-[((cyanoimino) { 1-[3-cyanic acid-3-methyl but-1-ene base]-5-isobutoxy-1H-pyrazoles-4-yl } methyl) amino]-1-adamantane esters;
2-(5-hydroxyl-2-adamantyl)-3-oxo-2,3-dihydro-1H-isoindole-1-subunit cyanamide and 2-(6-hydroxyl-2-adamantyl)-3-oxo-2,3-dihydro-1H-isoindole-1-subunit cyanamide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-4-[(pyridine-2-base alkylsulfonyl) methoxyl group] benzenyl amidine;
N'-cyanic acid-3-(cyclohexyl methoxyl group)-N-[5-(methylol)-2-adamantyl] benzenyl amidine;
N'-cyanic acid-N-(3-hydroxyl-1-adamantyl)-4-[(methyl sulphonyl) methoxyl group] benzenyl amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-N-methyl-3-(2-phenyl ethoxy) benzenyl amidine;
(3-hydroxyl-8-azabicyclo [3.2.1] suffering-8-yl) (9-methyl-9H-carbazole-3-yl) methylene radical cyanamide; With
1-(4-{ [2-(4-chlorophenoxy) phenyl] amino } piperidines-1-yl) the ethylidene cyanamide.
Bioactive mensuration
Abbreviation:EDTA: YD 30; Tris: three (hydroxymethyl) aminomethane; NADPH: Triphosphopyridine nucleotide, reduced.
The mensuration that suppresses constant:
In flicker approximate test test (SPA), the ability of evaluation test compound vitro inhibition people 11 β-HSD1 enzymic activity.At room temperature, cultivate Kendall compound substrate, NADPH cofactor and the titrating compound of tritiate with the people 11 β-HSD1 enzyme of brachymemma (24-287aa), so that be converted into hydrocortisone.Add nonspecific 11 β-HSD suppressor factor glycyrrhetinic acid, this reaction is stopped.Utilize anti-hydrocortisone monoclonal antibody and the SPA bead that scribbles anti-mouse antibodies to collect the hydrocortisone of tritiate.At room temperature shake Sptting plate, on scintillometer, measure then and combine with SPA bead bonded radio-labeling.In 96 hole microtiter plates, carry out 11 β-HSD1 and test (TV 220 μ L).For initial test, 188 μ L are comprised 75 nM 3The main mixture (master mix) of H-Kendall compound, 100 nM Kendall compounds and 181 μ M NADPH joins in the hole.In order to drive reaction, also add 1 mM Robison ester (G-6-P) and 1 U/mL G-6-P desaturase as the NADPH generation system with 11 β-reductase enzyme indication.Solid chemical compound is dissolved in the methyl-sulphoxide, prepares 10 mM deposit raw material, then use 10 times of methyl-sulphoxide serial dilutions.Each compound solution (in methyl-sulphoxide) is diluted 10 times in Tris/EDTA damping fluid (pH7.4).Then 22 μ L titration compounds (in duplicate) are joined in the substrate.0.1 mg/mL intestinal bacteria lysate (cross and express 11 β-HSD1 enzyme) through adding 10 μ L comes initiation reaction.After at room temperature plate being shaken and cultivates 30 minutes, come termination reaction through the 1 mM glycyrrhetinic acid that adds 10 μ L.The SPA bead that 1 μ M mono-clonal mouse anti hydrocortisone antibody through adding 10 μ L and 50 μ L scribble anti-mouse antibodies is collected product (hydrocortisone of tritiate).After shaking 30 minutes, in the Microbeta scintillometer, read plate.Based on background and peak signal, calculate and suppress per-cent.The hole that comprises substrate but do not contain compound or enzyme is as background, and thinks that the hole that comprises substrate and enzyme but do not comprise any compound is a peak signal.Calculate the inhibition per-cent of each compound with respect to peak signal, and form IC 50Curve.Suppose competitive inhibition, use the Cheng-Prusoff equation, by IC 50Value is calculated apparent Ki value.This test also can be used for 11 β-HSD2, wherein the hydrocortisone of 6 nM tritiates and 250 uM NAD +Be used separately as substrate and cofactor.
Compound of the present invention has activity in above-mentioned 11 β-HSD1 test, as shown in table 1.Nomenclature in the following table is following: A--Ki≤0.01 μ M; B--0.1 μ M>=Ki>0.01 μ M; C – 1 μ M>=Ki>0.1 μ M; And D--Ki>1 μ M; ND – does not measure.
The SPA test of table 1. people 11 β-HSD1 enzyme
Embodiment # Ki 11β-HSD1[μM] Embodiment # Ki 11β-HSD1[μM]
1 B 47 B
2 D 48 C
3 D 49 B
4 D 50 A
5 D 51 A
6 D 52 B
7 D 56 A
8 A 57 B
9 B 58 C
10 C 59 C
11 C 60 B
12 B 61 C
13 C 62 B
14 A 63 B
15 C 64 A
16 C 65 C
17 C 66 C
18 B 67 C
19 B 68 D
20 ND 69 B
21 B 70 A
22 D 71 B
23 C 72 D
24 B 73 C
25 B 74 A
27 A 75 B
28 C 76 D
29 C 77 C
30 D 78 B
31 C 79 B
33 C 80 A
35 D 81 D
36 C 82 B
37 B 83 C
38 B 84 C
39 D 85 C
40 D 86 B
41 B 87 D
42 C 88 C
43 B 89 B
45 A 93 D
46 D ? ?
Data in the table 1 show that in the SPA of above-mentioned people 11 β-HSD1 enzyme test, compound of the present invention is an active compound.11 beta-HSD 1 inhibitors of the present invention have the inhibition constant K i less than 600 nM usually, preferably less than 50 nM.
Should be appreciated that above-mentioned detailed description and embodiment only are illustrative, and be not considered to limit scope of the present invention.Various changes and modification to disclosed embodiment it will be apparent to those skilled in the art that (referring to, people such as Moreira for example, Current Med. Chem. 12,23-49 (2005); EP 1889842).This variation and improvement include but not limited to those and chemical structure, substituting group, verivate, midbody, synthetic, preparation and/or relevant variation and the improvement of method of use of the present invention, can under the situation that does not deviate from the spirit and scope of the present invention, carry out.This modification drops within the scope of additional claim.
All patents, patented claim and reference that this paper quotes, this paper combines its full content with the mode of quoting as proof.

Claims (20)

1. the compound of formula (I):
Figure 670208DEST_PATH_IMAGE001
(I),
Wherein
L is-(CH 2) n-or-(CR 38R 39) m-X-(CR 38R 39) n-or-(CR 38R 39) m-X-(CR 38R 39) n-Y-;
M is 0,1 or 2 when occurring at every turn independently;
N is 0,1 or 2 when occurring at every turn independently;
R 1Be naphthenic base or heterocycle;
R 2Be hydrogen, alkyl or aryl; R 1And R 2The atom that is connected with them forms heterocycle; Or R 2And R 3The atom that is connected with them forms heterocycle;
R 3And R 4Be hydrogen independently, alkyl or cycloalkyl; Or R 3And R 4The atom that is connected with them forms naphthenic base, heterocycle, heteroaryl or aryl;
R 5Be hydrogen, alkyl, amino, aryl, naphthenic base, heteroaryl or heterocycle, condition is: when L is-(CR 38R 39) m-X-(CR 38R 39) nDuring-Y-, R 5Not amino; Or R 4And R 5The atom that is connected with them forms naphthenic base or heterocycle;
X is-O-,-S-, and-S (O)-,-S (O) 2-,-NR 36-or-CR 36R 37-;
Y is O or NR 40
R 36And R 37Be hydrogen or alkyl independently when occurring at every turn; Or R 36And R 2The atom that is connected with them forms heterocycle;
R 38, R 39And R 40Be hydrogen or alkyl independently when occurring at every turn;
W is N-CN, N-OR 6, N-R 6Or S; With
R 6Be hydrogen, alkyl or aryl; Or
Its pharmacologically acceptable salt, ester, acid amides, N-oxide compound or prodrug.
2. the compound of claim 1, wherein R 1Be to be selected from following naphthenic base or heterocycle
Figure 587349DEST_PATH_IMAGE002
Figure 304769DEST_PATH_IMAGE003
。
3. the compound of claim 1, wherein R 5Be phenyl, pyridyl or heterocycle.
4. the compound of claim 1, wherein R 3And R 4Two all is hydrogen, or two all is alkyl.
5. the compound of claim 1, wherein R 3And R 4The atom that is connected with them forms naphthenic base, heterocycle, heteroaryl or aryl.
6. the compound of claim 5, wherein naphthenic base is (C 3-C 6) naphthenic base.
7. the compound of claim 1, wherein R 2And R 3The atom that is connected with them forms heterocycle.
8. the compound of claim 1, wherein L is-(CH 2) n-, wherein n is 0, or-(CR 38R 39) m-X-(CR 38R 39) n-, wherein two of m and n all be 0 and X be O.
9. the compound of claim 1, wherein R 4And R 5The atom that is connected with them forms naphthenic base or heterocycle.
10. the compound of claim 1, wherein R 36And R 2The atom that is connected with them forms heterocycle.
11. the compound of claim 1, wherein R 6It is alkyl or aryl.
12. the compound of claim 1 is selected from
(1E)-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl third amidine;
(1E)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-(2-aminomethyl phenyl) ethanamidine;
1-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] the tetramethylene carbonamidine;
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene base)-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-N'-cyanic acid-2-(2-fluorophenyl)-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-2-(2-chloro-pyridine-3-yl)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] ethanamidine;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyl-2-adamantyl]-2-methyl-prop amidine;
2-(4-chlorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide;
(1E)-N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methyl-formiate;
2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] thiopropionamide;
(1E)-2-(4-chlorophenoxy)-N'-methoxyl group-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine;
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
1-(3-chlorophenoxy)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl] the tetramethylene carbonamidine;
(E)-4-[(2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the sulfo-propionyl group) amino] diamantane-1-methyl-formiate;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate;
(1E)-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] third amidine;
N-[(E)-5-(amino-sulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy) phenoxy] thiopropionamide;
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the sulfo-propionyl group) amino] diamantane-1-methyl-formiate;
3-(4-chloro-phenyl-)-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine;
(1E)-3-(4-chloro-phenyl-)-N'-cyanic acid-N-[(E)-and 5-hydroxyl-2-adamantyl]-2,2-dimethyl propylene amidine;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the sulfo-propionyl group) amino] diamantane-1-formic acid;
(1E)-N'-cyanic acid-N-[(E)-5-cyanic acid-2-adamantyl]-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third amidine;
(E)-4-((1E)-and N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
(E)-4-[((1E)-N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
6-(4,4-dimethyl--1-[(E)-5-(methyl sulphonyl)-2-adamantyl]-5-sulfo-tetramethyleneimine-3-yl } methoxyl group) the cigarette nitrile;
(2Z)-and 4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--1-[(E)-and 5-(methyl sulphonyl)-2-adamantyl] tetramethyleneimine-2-subunit cyanamide;
(3S)-1-[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl]-N-cyclohexyl piperidines-3-thioamides;
(3S)-1-[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl]-N'-cyanic acid-N-cyclohexyl piperidines-3-carbonamidine;
(E)-4-{ [(1E)-and 2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
(1E)-2-(4-chlorophenoxy)-N'-cyanic acid-N-[(E)-5-cyanic acid-2-adamantyl]-2-methyl-prop amidine;
(1E)-and 2-(4-chlorophenoxy)-N'-cyanic acid-N-six hydrogen-2,5-first bridge pentalene-3a (1H)-Ji-2-methyl-prop amidine;
(1E)-and N-[(4s)-1-aza-tricycle [3.3.1.1 3,7] last of the ten Heavenly stems-the 4-yl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-1-azabicyclo [2.2.2] oct-3-yl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-encircles octyl group-2-methyl-prop amidine;
N-[outer-two rings [2.2.1] heptan-2-yl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(1E)-N-1-adamantyl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine;
2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] thiopropionamide;
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine;
2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] thiopropionamide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.2] octane-1-methane amides;
(E)-4-((1E)-2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methyl-formiate;
(E)-4-(2-[(1R*, 5S*, 6R*)-6-(4-chloro-phenyl-)-3-azabicyclo [3.2.0] heptan-3-yl]-2-methyl sulfo-propionyl group } amino) diamantane-1-methyl-formiate;
(1E)-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-2-phenoxy third amidine;
(E)-4-{ [(1E)-and N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } diamantane-1-methane amide;
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
(1E)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-methyl-prop amidine;
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
(1E)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
N-[(outward)-two ring [2.2.1] heptan-2-yl]-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
(1E)-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-methyl-prop amidine;
(1E)-N-(diamantane-1-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-encircles octyl group-2-methyl-prop amidine;
(1E)-N-[(E)-diamantane-2-yl]-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(E)-4-{ [(1E)-and 2-(4-chloro-2-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methyl-formiate;
(1E)-N'-cyanic acid-2-methyl-N-[(E)-5-(methyl sulphonyl) diamantane-2-yl]-2-phenoxy third amidine;
N'-cyanic acid-N-encircles octyl group-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
N-(outer-two rings [2.2.1] heptan-2-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[(E)-and 5-(methyl sulphonyl) diamantane-2-yl] third amidine;
(1E)-2-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-N-(six hydrogen-2,5-first bridge pentalene-3a (1H)-yl)-2-methyl-prop amidine;
(E)-4-{ [(1E)-and N-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
(1E)-N-[(3R, 5R)-diamantane-1-yl]-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
(1E)-N-(1-azabicyclo [2.2.2] oct-3-yl)-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-N-(six hydrogen-2,5-first bridge pentalene-3a (1H)-yl)-2-methyl-prop amidine;
(E)-4-{ [(1E)-and 2-(4-chloro-2-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
(E)-4-((1E)-and 2-[(5-chloro-pyridine-2-yl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
(E)-4-[(2-methyl-2-phenoxy tetrahydroform acyl group) amino] diamantane-1-methane amide;
(1E)-N'-cyanic acid-2-methyl-N-[(E)-5-(methyl sulphonyl) diamantane-2-yl]-2-(pyridine-2-base oxygen base) third amidine;
(1E)-N'-cyanic acid-N-[(E)-5-Cyanoadamantyl-2-yl]-2-(2-fluorophenoxy)-2-methyl-prop amidine;
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
(1E)-N'-cyanic acid-2-(2-fluorophenoxy)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.1] heptane-1-methane amides;
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.2] octane-1-methane amides;
N'-cyanic acid-N-(4-cyano-bicyclo [2.2.1] heptan-1-yl)-2-methyl-2-phenoxy third amidine;
N'-cyanic acid-N-(4-cyano-bicyclo [2.2.2] suffering-1-yl)-2-methyl-2-phenoxy third amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.2] suffering-1-yls]-2-methyl-prop amidine;
N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.2] suffering-1-yls]-2-methyl-2-phenoxy third amidine;
4-{ [N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group] amino } two ring [2.2.2] octane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } two ring [2.2.1] heptane-1-methane amides;
N'-cyanic acid-N-[4-(difluoromethyl) two ring [2.2.1] heptan-1-yl]-2-methyl-2-phenoxy third amidine;
2-(2-fluorophenoxy)-2-methyl-N-[(E)-and 5-sulfamyl diamantane-2-yl] third amidine;
2-(2-fluorophenoxy)-N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-prop amidine;
N-[(E)-5-hydroxyadamantane-2-yl]-2-methyl-2-phenoxy third amidine;
5-chloro-N'-cyanic acid-N-[(E)-5-hydroxyadamantane-2-yl]-2-anisole carbonamidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(4-hydroxyl two ring [2.2.2] suffering-1-yls)-2-methyl-prop amidine;
N'-cyanic acid-N-(4-hydroxyl two ring [2.2.2] suffering-1-yls)-2-methyl-2-phenoxy third amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(4-cyano-bicyclo [2.2.2] suffering-1-yl)-2-methyl-prop amidine;
N'-cyanic acid-N-(4-hydroxyl two ring [2.2.1] heptan-1-yl)-2-methyl-2-phenoxy third amidine;
4-({ 2-[(4-benzyl chloride base) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(methyl sulphonyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(pyridine-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-cyanobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [2-fluoro-4-(trifluoromethyl) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [4-(difluoro-methoxy) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-{ [4-(difluoro-methoxy) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-({ 2-[(4-chloro-2-luorobenzyl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[(4-chloro-2-luorobenzyl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-{ [2-fluoro-4-(trifluoromethyl) benzyl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(pyridine-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-[(2-{ [2-bromo-4-(trifluoromethyl) benzyl] oxygen base }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 6-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2, the 3-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(3, the 4-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [2-(benzyloxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(3, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(3-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2, the 6-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2-cyanobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 3-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(4-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[(3-benzyl chloride base) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-ar-isopropyl benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[(4-methyl-benzyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methyl-formiate;
4-{ [2-(1,3-benzodioxole-5-ylmethoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2, the 4-dichloro benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(2-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-cyanobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ 2-[(4-tertiary butyl benzyl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(4-methyl-benzyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-methoxybenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(6-picoline-2-yl) methoxyl group] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[(6-picoline-2-yl) methoxyl group] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-luorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethoxy) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(quinolin-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{ [4-(trifluoromethyl) benzyl] oxygen base } cyclobutyl) methyl] amino } diamantane-1-methyl-formiate;
4-({ N-cyanic acid-2-[(2, the 4-dichloro benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(quinolin-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[(4-ar-isopropyl benzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(3-methyl-benzyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(2, the 5-difluorobenzyl) oxygen base]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{ [4-(difluoro-methoxy) benzyl] oxygen base } cyclopropyl) methyl] amino } diamantane-1-formic acid;
4-({ (cyanoimino) [1-(quinoline-8-ylmethoxy) cyclopropyl] methyl } amino) diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{ [4-(difluoro-methoxy) benzyl] oxygen base } cyclopropyl) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [1-(quinoline-8-ylmethoxy) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{ [4-(trifluoromethyl) benzyl] oxygen base } cyclobutyl) methyl] amino } diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{ [4-(trifluoromethyl) benzyl] oxygen base } cyclobutyl) methyl] amino } diamantane-1-methane amide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } ethanamidine;
N'-cyanic acid-2-(2,6-thebaine-4-yl)-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(4-hydroxy piperidine-1-yl) third amidine;
2-azepan-1-base-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
Carboxylamine 4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino]-the 1-adamantane esters;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino]-1-adamantyl acetic ester;
N-{4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino]-the 1-adamantyl } ethanamide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-fluoro-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } ethanamidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-[4-(5-picoline-2-yl) piperazine-1-yl] third amidine;
2-{ [2-(4-chloro-phenyl-) ethyl] amino }-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
2-(4-benzyl piepridine-1-yl)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(6; 7; 9; 10-tetrahydrochysene-8H-[1,3] dioxole is [4,5-g] [3] benzo-aza -8-yl also) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(4-pyridine-2-base piperazine-1-yl) third amidine;
N'-cyanic acid-2-[4-(4-fluorophenyl) piperazine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-[4-(4-p-methoxy-phenyl) piperazine-1-yl] third amidine;
N'-cyanic acid-2-[4-(5-cyanopyridine-2-yl) piperazine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[4-(2-furoyl) piperazine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-(1,3-dihydro-2H-isoindole-2-yl)-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[4-(trifluoromethyl) phenyl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
2-[3-(4-chlorophenoxy) azetidine-1-yl]-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[4-(2-fluorophenoxy) piperidines-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[3-(2-fluorophenoxy) piperidines-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[3-(3-fluorophenoxy) tetramethyleneimine-1-yl]-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-2-[[2-(3, the 4-dichlorophenyl) ethyl] (methyl) amino]-N-(5-hydroxyl-2-adamantyl) third amidine;
2-[[2-(4-chloro-phenyl-)-1-methylethyl] (methyl) amino]-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
2-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
2-[4-(6-chloro-pyridine-3-yl) piperazine-1-yl]-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl) third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-(3-phenyl azetidine alkane-1-yl) third amidine;
N'-cyanic acid-N-[5-(methylol)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N-methyl adamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N-methoxyl group diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N-hydroxyadamantane-1-methane amide;
N-[5-(aminomethyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-1-{ [4-(trifluoromethyl) benzyl] amino } the Trimetylene carbonamidine;
4-({ N-cyanic acid-2-methyl-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-1-piperidines-1-basic ring propane carbonamidine;
N'-cyanic acid-2-methyl-N-[5-(5-methyl isophthalic acid; 2,4- diazole-3-yl)-the 2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
N'-cyanic acid-2-methyl-N-[5-(2H-tetrazolium-5-yl)-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-[(2-{4-[[(4-chloro-phenyl-) alkylsulfonyl] (cyclopropyl) amino] piperidines-1-yl }-N-cyanic acid tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] third amidine;
4-{ [N-cyanic acid-2-(3-fluoropyrrolidine-1-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3-fluoropyrrolidine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methyl-formiate;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(2-methyl-4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ 2-[4-(5-chloro-pyridine-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) ethyliminum acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] ethyliminum acyl group } amino) diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclopropyl) methyl] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-methane amide;
N'-cyanic acid-2-methyl-N-[5-(4H-1,2,4-triazole-3-yl)-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(2-furyl methyl) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(pyridin-4-yl methyl) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclopropyl) methyl] amino } diamantane-1-methane amide;
4-({ 2-[4-(4-chloro-phenyl-) piperidines-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-Phenylpiperidine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(1; 2; 4,5-tetrahydrochysene-3H-3-benzo-aza -3-yl) the tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[4-(trifluoromethyl) phenyl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-[2-(trifluoromethyl) tetramethyleneimine-1-yl] ethyliminum acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) ethyliminum acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[2-methyl-4-(5-picoline-2-yl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3-fluorine piperidines-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-{2-(trifluoromethyl)-4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(5-fluorine pyridin-3-yl)-1,4-Diazesuberane-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-cyclopropyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-formic acid;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclobutyl) methyl] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{5-[3-(trifluoromethyl) phenyl]-1,5-diazacyclo octane-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(3-aminomethyl phenyl)-1,4-Diazesuberane-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-phenoxy tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ 2-[7-(5-pyridine bromide-2-yl)-3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ 2-[5-(6-chloro-pyridine-3-yl) hexahydropyrrolo is [3,4-c] pyrroles-2 (1H)-yl also]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(3-pyridin-3-yl-3,9-diazabicyclo [4.2.1] ninth of the ten Heavenly Stems-9-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-([(4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } methyl) phenylformic acid;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-cyclopropyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the ethyliminum acyl group) amino] diamantane-1-methane amide;
4-{ [(cyanoimino) (1-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } cyclobutyl) methyl] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(2-methylcyclohexyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[(3-methylcyclohexyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(suberyl oxygen base)-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(cyclohexyl methoxyl group)-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-{ [2-(benzyloxy)-N-cyanic acid ethyliminum acyl group] amino } diamantane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(1,3-thiazoles-5-ylmethyl) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(2-methoxybenzyl) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-N-(3, the 4-dimethoxy-benzyl) diamantane-1-methane amide;
4-({ 2-[9-(6-chloro-pyridine-3-yl)-3,9-diazabicyclo [4.2.1] ninth of the ten Heavenly Stems-3-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(2-anilino-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2, the 3-dichlorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-phenylpiperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(4-aminomethyl phenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(1,3-benzothiazole-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(3, the 4-dichlorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(3-aminomethyl phenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[2-(trifluoromethyl) phenyl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2,4 difluorobenzene base) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(6-picoline-2-yl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-pyrimidine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[3-(trifluoromethyl) phenyl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[3-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ 2-[4-(3-chloro-phenyl-) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(4-acetylphenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N, N-dimethyladamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclobutyl] (cyanoimino) methyl] amino } diamantane-1-formic acid;
4-{ [(cyanoimino) (1-phenycyclopropyl) methyl] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-phenyl tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(4-methylcyclohexyl) oxygen base] tetrahydroform acyl group } amino) diamantane-1-methane amide;
N-{4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } ethanamide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyrimidine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyrazine-2-base piperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(4-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(3-cyanopyridine-2-yl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(6-picoline-3-yl)-1,4-Diazesuberane-1-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[(2-{4-[3-chloro-5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-[(N-cyanic acid-2-phenoxy tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [2-(benzyloxy)-N-cyanic acid ethyliminum is for acyl group] amino } diamantane-1-methane amide;
4-(2-{ [(4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } ethyl) phenylformic acid;
4-{ [N-cyanic acid-2-methyl-2-(2-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [2-(2-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-phenyl tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [(cyanoimino) (1-phenycyclopropyl) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclobutyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
N'-cyanic acid-N-{5-[(methyl sulphonyl) amino]-2-adamantyl }-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [N-cyanic acid-2-(2-methoxyl group phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(4-methoxyl group phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[3-(trifluoromethyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-(1-hydroxyl-1-methylethyl)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [N-cyanic acid-2-methyl-2-(4-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [2-(3-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(tetrahydrochysene-2H-pyrans-2-ylmethoxy) tetrahydroform acyl group] amino } diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(4-phenylpiperazine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3-methoxyl group phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(trifluoromethoxy) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2-p-methoxy-phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[methyl (phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2, the 4-Dimethoxyphenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(cyclohexyl methoxyl group)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2,3-dicyano phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-(cyano methyl)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-({ N-cyanic acid-2-methyl-2-[4-(4-nitrophenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-prop amidine;
4-({ N-cyanic acid-2-[4-(2,4 dichloro benzene base) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
N-2-adamantyl-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-2-adamantyl-N'-cyanic acid-2-methyl-2-phenyl third amidine;
N-2-adamantyl-N'-cyanic acid-1-benzyl ring propane carbonamidine;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } acetate;
4-({ 2-[4-(4-chloro-2-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(N-cyanic acid-2-methyl-2-{4-[4-(trifluoromethyl) pyrimidine-2-base] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ 2-[4-(3-chloro-4-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(4-bromophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(5-chloro-2-p-methoxy-phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-phenyl-) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2-cyano-phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(2-aminomethyl phenyl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(4-chloro-phenyl-) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
6-[(1-suberyl-4,4-dimethyl--5-oxo-pyrrolidine-3-yl) methoxyl group] cigarette nitrile;
4-({ 2-[4-(3-chloro-pyridine-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(2-{4-[2-chloro-4-(trifluoromethyl) phenyl] piperazine-1-yl }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-{ [N-cyanic acid-2-(3-fluoropyrrolidine-1-yl)-2-methyl-prop imines acyl group] amino }-N-(pyridin-3-yl methyl) diamantane-1-methane amide;
4-({ 2-[(4-chloro-phenyl-) sulfenyl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(3-Phenylpiperidine-1-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ 2-[4-(2-chloro-4-aminomethyl phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [2-(3-bromine phenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
1-suberyl-4-{ [(2-fluorophenyl) (methyl) amino] methyl }-3,3-dimethyl pyrrolidine-2-ketone;
4-({ N-cyanic acid-2-[4-(2-fluorophenyl) piperidines-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(2-aminomethyl phenyl) piperidines-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-4-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-([(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } methyl) phenylformic acid;
4-{ [2-({ 1-[(benzyloxy) carbonyl] piperidin-4-yl } methoxyl group)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(2-furoyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-4-cyano-phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloro-4-fluorophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
1-suberyl-3,3-dimethyl--4-(phenoxymethyl) pyrrolidin-2-one;
4-{ [[1-(4-chloro-phenyl-) cyclohexyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclopropyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(4-chloro-phenyl-) cyclopentyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [2-(4-chloro-phenyl-)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [(cyanoimino) (1-benzyl ring amyl group) methyl] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(2, the 3-dimethyl phenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
Carboxylamine 4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantane esters;
4-[(2-{4-[(4-chloro-phenyl-) alkylsulfonyl] piperazine-1-yl }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-formic acid;
4-{ [2-(benzyloxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
4-(4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--2-oxo-pyrrolidine-1-yl) azepan-1-methane amide;
4-({ N-cyanic acid-2-[4-(2,4 difluorobenzene base) piperidines-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
6-{ [1-(5-hydroxyl ring octyl group)-4,4-dimethyl--5-oxo-pyrrolidine-3-yl] methoxyl group } the cigarette nitrile;
4-({ N-cyanic acid-2-[4-(4-cyanic acid-2-fluorophenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-(2-(cyanoimino)-4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl pyrrolidine-1-yl) diamantane-1-methane amide;
9-(4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--2-oxo-pyrrolidine-1-yl) two ring [3.3.1] nonane-3-methane amides;
N-[4-(amino-sulfonyl) benzyl]-4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-[2-{ [5-(aminocarboxyl)-2-adamantyl] amino }-2-(cyanoimino)-1,1-dimethyl-oxyethyl group] the phenylcarbamic acid tertiary butyl ester;
4-(4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl--2-oxo-pyrrolidine-1-yl) two ring [5.1.0] octane-8-ethyl formates;
N-[4-(aminocarboxyl) benzyl]-4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
[(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] glycocoll;
3-([(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) carbonyl] amino } methyl) phenylformic acid;
4-({ (cyanoimino) [1-(3-fluorophenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-{ [[1-(2-chloro-4-fluorophenyl) cyclopentyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-fluorophenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(2-fluorophenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-{ [(cyanoimino) (1-methylcyclohexyl) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [1-(2,4 dichloro benzene base) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-p-methoxy-phenyl) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-aminomethyl phenyl) cyclopropyl] methyl } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{3-methyl-4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl)-3,5-dimethyl--1H-pyrazol-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl)-3,5-dimethyl--1H-pyrazol-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
6-{ [4,4-dimethyl--1-(4-methyl bicyclic [2.2.2] suffering-1-yl)-5-oxo-pyrrolidine-3-yl] methoxyl group } the cigarette nitrile;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridin-4-yl phenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
6-{ [1-(5-cyanic acid ring octyl group)-4,4-dimethyl--5-oxo-pyrrolidine-3-yl] methoxyl group } the cigarette nitrile;
4-[(N-cyanic acid-2-methyl-2-thiophene-2-base tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-thiene-3-yl-tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[5-(trifluoromethyl) pyridine-2-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] phenyl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ 2-[4-chloro-2-(tetramethyleneimine-1-base alkylsulfonyl) phenoxy]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(methyl sulphonyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [1-(4-p-methoxy-phenyl) cyclopentyl] methyl } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[(3-aminomethyl phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[2-{ [5-(aminocarboxyl)-2-adamantyl] amino }-2-(cyanoimino)-1, the 1-dimethyl ethyl] piperazine-1-formic acid tertiary butyl ester;
N'-cyanic acid-2-(3-fluoropyrrolidine-1-yl)-N-(5-hydroxyl-2-adamantyl) third amidine;
4-({ N-cyanic acid-2-methyl-2-[2-(methyl sulphonyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ 2-[4-(2-bromophenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-{ [2-(4-bromophenyl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ 2-[(3-chloro-phenyl-) amino]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(3-p-methoxy-phenyl) amino]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(4-cyano-phenyl)-3,5-dimethyl--1H-pyrazol-1-yl]-2-methyl-prop imines acyl group } amino)-N-(1,3-thiazoles-5-ylmethyl) diamantane-1-methane amide;
4-({ 2-[4-(6-chloropyrimide-4-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(6-chlorine pyridazine-3-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(2-chloropyrimide-4-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-[(2-{4-chloro-2-[(diethylamino) alkylsulfonyl] phenoxy }-N-cyanic acid-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
N-[(4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } amino) carbonyl] glycocoll;
4-({ N-cyanic acid-2-[4-(5-cyanopyridine-2-yl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ 2-[4-(3-chloro-5-cyanopyridine-2-yl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(1,3-thiazoles-2-yl) piperazine-1-yl] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-({ 2-[(5-pyridine bromide-2-yl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
1-(5-cyanic acid-2-adamantyl)-4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl pyrrolidine-2-subunit cyanamide;
4-({ N-cyanic acid-2-methyl-2-[4-(tetramethyleneimine-1-base alkylsulfonyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) amino]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [4-(dimethylamino) phenyl] amino }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) phenyl] amino } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [3-(trifluoromethyl) phenyl] amino } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl isophthalic acid-(2-methyl-benzyl)-2-oxo-piperidine-3-yl] methyl } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(2-cyano-benzene oxygen)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-(2-(cyanoimino)-3,3-dimethyl--4-{ [4-(1H-1,2,4-triazol-1-yl) phenoxy] methyl } tetramethyleneimine-1-yl) diamantane-1-methane amide;
4-(2-(cyanoimino)-4-{ [4-(1H-imidazoles-1-yl) phenoxy] methyl }-3,3-dimethyl pyrrolidine-1-yl) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(2-hydroxy phenyl) piperazine-1-yl]-2-methyl-prop imines acyl group } amino) diamantane-1-formic acid;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-2-methyl-prop amidine;
4-[2-{ [5-(aminocarboxyl)-2-adamantyl] amino }-2-(cyanoimino)-1, the 1-dimethyl ethyl]-N-(tertiary butyl) piperazine-1-methane amide;
4-{ [N-cyanic acid-2-(4-hydroxyphenoxy)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) sulfenyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-(formamido group)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-{ [(1-benzyl-3-methyl-2-oxo-pyrrolidine-3-yl) (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl isophthalic acid-(2-methyl-benzyl)-2-oxo-pyrrolidine-3-yl] methyl } amino) diamantane-1-methane amide;
4-{ [[1-(2-benzyl chloride base)-3-methyl-2-oxo-pyrrolidine-3-yl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [[1-(3-benzyl chloride base)-3-methyl-2-oxo-pyrrolidine-3-yl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(2H-tetrazolium-5-yl)-2-adamantyl] third amidine;
4-({ N-cyanic acid-2-methyl-2-[4-(1-methyl isophthalic acid H-pyrazoles-4-yl) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methylthio group)-2-adamantyl] third amidine;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methylsulfinyl)-2-adamantyl] third amidine;
4-{ [2-(3-bromophenyl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-[4-(3,5-dimethyl-different
Figure 40064DEST_PATH_IMAGE005
azoles-4-yl) phenyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-pyridin-3-yl phenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [({ 4-[(N-cyanic acid-2-methyl-2-thiophene-2-base tetrahydroform acyl group) amino]-1-adamantyl } carbonyl) amino] methyl } phenylformic acid;
4-({ N-cyanic acid-2-methyl-2-[4-(1H-pyrazoles-4-yl) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N-(4-{ [(methyl sulphonyl) amino] carbonyl } benzyl) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) sulfinyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-[(4-p-methoxy-phenyl) alkylsulfonyl]-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl isophthalic acid-(1-methyl isophthalic acid-styroyl)-2-oxo-pyrrolidine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(1-styroyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
2-(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) ethanamide;
4-{ [N-cyanic acid-2-methyl-2-(1,3-thiazoles-2-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [[1-(4-benzyl chloride base)-3-methyl piperidine-3-yl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(4-hydroxy phenyl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl]-N'-hydroxyadamantane-1-carbonamidine;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl] diamantane-1-methane amide;
4-{ [(1-benzyl-3-methyl-2-oxo-piperidine-3-yl) (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(4-Phenoxyphenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) acetate;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl] diamantane-1-carbonamidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(2H-tetrazolium-5-ylmethyl)-2-adamantyl] third amidine;
4-{ [2-(1-thionaphthene-3-yl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
N-{5-[(amino-sulfonyl) methyl]-2-adamantyl }-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [[1-(4-chlorophenoxy) cyclobutyl] (cyanoimino) methyl] amino } diamantane-1-methane amide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N'-hydroxyadamantane-1-carbonamidine;
4-[([(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) methyl] alkylsulfonyl } amino) methyl] phenylformic acid;
2-(4-chlorophenoxy)-N'-cyanic acid-N-[5-(1H-imidazoles-2-yl)-2-adamantyl]-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-(5-fluorine pyridine-2-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
3-(4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) vinylformic acid;
4-[(N-cyanic acid-2-methyl-2-{ [5-(1H-pyrazol-1-yl) pyridine-2-yl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
2-(4-chlorophenoxy)-N'-cyanic acid-N-(5-different
Figure 238965DEST_PATH_IMAGE005
azoles-5-base-2-adamantyl)-2-methyl-prop amidine;
4-[(N-cyanic acid-2-methyl-2-quinoxaline-2-base tetrahydroform acyl group) amino] diamantane-1-methane amide;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-{5-[(2-morpholine-4-base oxethyl) methyl]-2-adamantyl } third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-(2-methylphenoxy) third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-(4-methylphenoxy) third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-[2-(trifluoromethyl) phenoxy] third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-[2-(trifluoromethoxy) phenoxy] third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N'-cyanic acid-N-[5-(1-hydroxyethyl)-2-adamantyl]-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
2-{4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-the 1-adamantyl } propionic acid;
4-[(N-cyanic acid-3-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-methane amide;
(2R)-and N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the fourth amidine;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-formic acid;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-formic acid;
4-[((2R)-N-cyanic acid-3-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino] diamantane-1-formic acid;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-N, N-dimethyladamantane-1-methane amide;
4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino]-N, N-dimethyladamantane-1-methane amide;
N-{4-[((2R)-N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino]-the 1-adamantyl } ethanamide;
N-{4-[((2R)-N-cyanic acid-3-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } fourth imines acyl group) amino]-the 1-adamantyl } ethanamide;
N'-cyanic acid-2-(3,3-difluoro piperidines-1-yl)-N-[5-hydroxyl-2-adamantyl] third amidine;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-[(3S)-and 3-(trifluoromethyl) tetramethyleneimine-1-yl] ethanamidine;
4-(N-cyanic acid-2-[(3R)-and 3-fluorine piperidines-1-yl] the tetrahydroform acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-methoxyl group-2-adamantyl]-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
4-[(N-cyanic acid-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } penta imines acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(thiophenyl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[methyl (phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-formic acid;
4-{ [N-cyanic acid-2-methyl-2-(2-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-methyl-2-(3-methylphenoxy) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[methyl (phenyl) amino] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ 2-[(4-chloro-phenyl-) amino]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-{ [2-(2-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3,3-difluoro piperidines-1-yl) fourth imines acyl group] amino } diamantane-1-methane amide;
4-[3-benzyl-2-(cyanoimino) tetramethyleneimine-1-yl] diamantane-1-methane amide;
4-({ 2-[4-(2-chloro-4-cyano-phenyl) piperazine-1-yl]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-methyl-2-phenyl third amidine;
2-(4-chloro-phenyl-)-N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-methyl-prop amidine;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-1-benzyl ring propane carbonamidine;
4-{ [2-(4-bromo-3,5-dimethyl--1H-pyrazol-1-yl)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-(2-(cyanoimino)-4-{ [(5-cyanopyridine-2-yl) oxygen base] methyl }-3,3-dimethyl pyrrolidine-1-yl) diamantane-1-methane amide;
4-{ [2-(4-chlorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N-methyl adamantane-1-methane amide;
4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4'-(methyl sulphonyl)-1,1'-biphenyl-4-yl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(3-cyanopyridine-2-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[2-(trifluoromethoxy) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[4-(trifluoromethyl) pyridine-2-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ 2-[(5-pyridine bromide-2-yl) oxygen base]-N-cyanic acid-2-methyl-prop imines acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[2-(trifluoromethyl) phenoxy] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-(2-(cyanoimino)-3,3-dimethyl--4-{ [4-(1H-1,2,4-triazol-1-yl) phenoxy] methyl } tetramethyleneimine-1-yl) diamantane-1-methane amide;
4-{ [(cyanoimino) (2-aminomethyl phenyl) methyl] amino } diamantane-1-methane amide;
4-{ [2-(3-bromo-4-methoxyl group phenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-{ [2-(2-bromo-4-methoxyl group phenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(pyridine-2-ylmethyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(pyridin-3-yl methyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(pyridin-4-yl methyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(2-pyridine-2-base ethyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-{ [N-cyanic acid-3-(4-p-methoxy-phenyl)-2,2-dimethyl--3-oxo tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) phenyl] amino } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethoxy) phenyl] sulfenyl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[2-(cyanoimino)-3,3-dimethyl--4-({ [5-(trifluoromethyl) pyridine-2-yl] oxygen base } methyl) tetramethyleneimine-1-yl] diamantane-1-methane amide;
4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-N, N-dimethyladamantane-1-methane amide;
4-({ (cyanoimino) [3-methyl-2-oxo-1-(1-pyridine-2-base ethyl) tetramethyleneimine-3-yl] methyl } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[3-(1,3-thiazoles-4-ylmethoxy) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[3-(2-morpholine-4-base oxethyl) phenyl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
N-[5-(5-amino-4H-1,2,4-triazole-3-yl)-2-adamantyl]-2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-(6-fluorine pyridin-3-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
2-(4-chlorophenoxy)-N'-cyanic acid-N-[5-(methylol)-2-adamantyl]-2-methyl-prop amidine;
4-{ [N-cyanic acid-2-methyl-2-(6-morpholine-4-yl pyridines-3-yl) tetrahydroform acyl group] amino } diamantane-1-methane amide;
4-{ [N-cyanic acid-2-(5-fluorine pyridine-2-yl)-2-methyl-prop imines acyl group] amino } diamantane-1-methane amide;
4-({ N-cyanic acid-2-methyl-2-[6-(methylamino) pyridin-3-yl] tetrahydroform acyl group } amino) diamantane-1-methane amide;
4-[(N-cyanic acid-2-{ [5-(1H-imidazoles-1-yl) pyridine-2-yl] oxygen base }-2-methyl-prop imines acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [5-(1H-pyrazol-1-yl) pyridine-2-yl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-quinoxaline-2-base tetrahydroform acyl group) amino] diamantane-1-methane amide;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(3-chlorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-methyl-2-(3-methylphenoxy) third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2-methoxyl group phenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(3-methoxyl group phenoxy)-2-methyl-prop amidine;
(2S)-amino (4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) acetate;
2-[(4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) alkylsulfonyl] ethanamide;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-2-methyl-2-(4-nitrophenyl) third amidine;
N'-cyanic acid-N-[5-(methyl sulphonyl)-2-adamantyl]-1-benzyl ring propane carbonamidine;
2-[(4-pyridine bromide-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
(2S)-2-(4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) propionic acid;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(1,1'-biphenyl-2-base oxygen base)-N'-cyanic acid-2-methyl-prop amidine;
4-{ [2-(1,1'-biphenyl-2-base oxygen base)-N-cyanic acid-2-methyl-prop imines acyl group] amino } diamantane-1-formic acid;
N'-cyanic acid-2-(2,4 dichloro benzene oxygen base)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(2-bromo-4-fluorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-2-(2-methylphenoxy)-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-2-(4-methylphenoxy)-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(2-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(4-methoxyl group phenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-cyano-benzene oxygen)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-methoxyl group phenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
2-[(3-pyridine bromide-2-yl) oxygen base]-N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-bromo-4-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N'-cyanic acid-N-[5-hydroxyl-2-adamantyl]-3-methyl-2-oxo-1-pyridine-2-base tetramethyleneimine-3-carbonamidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-{5-[(methylthio group) methyl]-2-adamantyl } third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,4 dichloro benzene oxygen base)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2, the 4-dimethyl phenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(4-fluoro-2-methylphenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,6-two chloro-4-methylphenoxy)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,6-two chloro-4-fluorophenoxies)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(4-chloro-2-fluorophenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-2-(2-chloro-4-methylphenoxy)-N'-cyanic acid-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(mesityloxy)-2-methyl-prop amidine;
2-(4-chlorophenoxy)-N'-cyanic acid-2-methyl-N-{5-[(methyl sulphonyl) methyl]-2-adamantyl } third amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-prop amidine;
N-[5-(amino-sulfonyl)-2-adamantyl]-N'-cyanic acid-2-(4-fluorophenoxy)-2-methyl-prop amidine;
N'-cyanic acid-2-(2,4 difluorobenzene oxygen base)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-sec.-propyl phenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(4-fluoro-2-methylphenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2-fluorophenoxy)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl]-2-[2-(trifluoromethyl) phenoxy] third amidine;
4-{ [(cyanoimino) (3-methyl-2-oxo-1-pyridine-2-base tetramethyleneimine-3-yl) methyl] amino } diamantane-1-methane amide;
(2S)-2-amino-2-(4-{ [2-(2-chloro-4-fluorophenoxy)-N-cyanic acid-2-methyl-prop imines acyl group] amino }-the 1-adamantyl) ethanamide;
N'-cyanic acid-2-[4-fluoro-2-(1H-pyrazol-1-yl) phenoxy]-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-(2,6-two chloro-4-fluorophenoxies)-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-[4-fluoro-2-(1H-pyrazoles-4-yl) phenoxy]-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl] third amidine;
N'-cyanic acid-2-methyl-N-[5-(methyl sulphonyl)-2-adamantyl]-2-[3-(trifluoromethoxy) phenoxy] third amidine;
3-deuterium generation-4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino]-7-deuterium generation-diamantane-1-methane amide;
N-[1-deuterium generation-4-adamantyl]-N'-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third amidine;
3-deuterium generation-4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
4-[(N-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } the tetrahydroform acyl group) amino]-7-deuterium generation-diamantane-1-methane amide;
N-[1-deuterium generation-4-adamantyl]-N'-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine;
3-[(N-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } the tetrahydroform acyl group) amino] diamantane-1-methane amide;
N-1-azabicyclo [2.2.2] oct-3-yl-N'-cyanic acid-2-methyl-2-{ [4-(trifluoromethyl) benzyl] oxygen base } third amidine;
N-[1-aza-tricycle [3.3.1.13,7] last of the ten Heavenly stems-4-yl]-N'-cyanic acid-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine; With
N'-cyanic acid-N-cyclohexyl-2-methyl-2-{4-[5-(trifluoromethyl) pyridine-2-yl] piperazine-1-yl } third amidine.
13. be selected from following compound:
{ 4-[(4-aminomethyl phenyl) alkylsulfonyl] piperazine-1-yl } (4-nitrophenyl) methylene radical cyanamide;
N'-cyanic acid-N-{1-[(1-cyanic acid cyclopropyl) methyl] piperidin-4-yl }-N-cyclopropyl-4-(2,2,2-three fluoro-1-hydroxyl-1-methylethyls) benzenyl amidine;
Carboxylamine [4-[{ (cyanoimino) [4-(2,2,2-three fluoro-1-hydroxyl-1-methylethyls) phenyl] methyl } (cyclopropyl) amino]-1-(4-fluorophenyl) cyclohexyl] methyl ester;
N'-cyanic acid-N-cyclopropyl-N-[4-(2-hydroxyethyl) cyclohexyl]-4-isopropyl benzene carbonamidine; [5-(4-aminomethyl phenyl) different
Figure 845526DEST_PATH_IMAGE005
azoles-4-yl] (3-pyridin-3-yl tetramethyleneimine-1-yl) methylene radical cyanamide;
4-[4-[(the 1-adamantyl is amino) (cyanoimino) methyl]-5-(1-methyl cyclopropyl)-1H-pyrazol-1-yl] phenylformic acid;
N'-cyanic acid-N-cyclohexyl-2-[(2-styroyl) sulfenyl] pyridine-3-carbonamidine;
4-[5-[(the 2-adamantyl is amino) (cyanoimino) methyl]-6-(rosickyite base) pyridine-2-yl] morpholine-2-formic acid;
N'-cyanic acid-N-cyclopropyl-N-(4-cyclopropyl-4-hydroxy-cyclohexyl)-4-(2,2,2-three fluoro-1-hydroxyl-1-methylethyls) benzenyl amidine;
2-[2-(4-fluorophenyl)-6-hydroxyl-2-adamantyl]-1-(3-hydroxy azetidine-1-yl) ethylidene cyanamide;
2-{1-[2-(the 2-adamantyl is amino)-2-(cyanoimino) ethyl] cyclopentyl }-N-isobutyl-ethanamide;
2-{4-[(2-fluorophenyl) alkylsulfonyl]-1,4-Diazesuberane-1-yl }-1-octahydro quinoline-1 (2H)-Ji ethylidene cyanamide;
1-cyclohexyl-3-[(3,5-two chloro-4'-{ [4-(2-fluoro ethyl) piperazine-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl] tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-piperidines-1-base tetramethyleneimine-2-subunit cyanamide;
3-cyclohexyl-1-[(3,5-two chloro-4'-{ [4-(2-fluoro ethyl) piperazine-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl] tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-(4,4-difluoro cyclohexyl) tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-fluoro-1,1'-biphenyl-4-yl) methyl]-1-(4,4-difluoro cyclohexyl) tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-(4-hydroxy piperidine-1-yl) tetramethyleneimine-2-subunit cyanamide;
4-{2-(cyanoimino)-3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl] tetramethyleneimine-1-yl } piperidines-1-methyl-formiate;
2-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-2-azaspiro [4.5] last of the ten Heavenly stems-1-subunit cyanamide;
3-[(3,5-two chloro-4'-{ [4-(trifluoromethyl) piperidines-1-yl] carbonyl }-1,1'-biphenyl-4-yl) methyl]-1-(4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline-6-yl) tetramethyleneimine-2-subunit cyanamide;
3-[(3,5-two chloro-4'-fluoro-1,1'-biphenyl-4-yl) methyl]-1-(4,5,6,7-tetrahydrochysene-2H-indazole-5-yl) tetramethyleneimine-2-subunit cyanamide;
N-2-adamantyl-2'-the tertiary butyl-N'-cyanic acid-2'H-1,3'-joins pyrazoles-4'-carbonamidine;
2-(4-bromo-2-fluorophenyl)-2-hydroxyl-1-(3-oxo-1'H, 3H-spiral shell [2-cumarone-1,3'-tetramethyleneimine]-1'-yl) ethylidene cyanamide;
N'-cyanic acid-N-(1-{ [4-(2, the 5-3,5-dimethylphenyl) piperazine-1-yl] carbonyl } piperidines-3-yl)-4-hydroxyadamantane-1-carbonamidine;
1-{3-[1-(4-chloro-phenyl-) cyclopropyl]-1-oxa--2,7-diaza spiro [4.4] ninth of the ten Heavenly Stems-2-alkene-7-yl } the ethylidene cyanamide;
7-(2-chloro-phenyl-)-1-isobutyl--1,7-diaza spiro [4.4] ninth of the ten Heavenly Stems-6-subunit cyanamide;
8-(3-chloro-pyridine-2-yl)-2-cyclohexyl-2,8-diaza spiro [4.5] last of the ten Heavenly stems-1-subunit cyanamide;
5-{4-[1-(cyanoimino)-2-(4-hydroxy-cyclohexyl)-2,7-diaza spiro [4.5] last of the ten Heavenly stems-7-yl]-3-fluorophenyl }-N, N-lutidine-2-methane amide;
2-(2-acetylphenyl)-N'-cyanic acid-N-encircles octyl group-1,3-thiazoles-4-carbonamidine;
(5-cyclopropyl-1-piperidin-4-yl-1H-pyrazoles-4-yl) { 3-[2-(trifluoromethyl) phenyl] tetramethyleneimine-1-yl } methylene radical cyanamide;
2-[4-(2-{ [(4-chloro-phenyl-) (cyanoimino) methyl] amino } ethyl) phenoxy]-2 Methylpropionic acid;
1'-{ [2-(trifluoromethyl) phenoxy] ethanoyl } spiral shell [indoles-3,4'-piperidines]-2 (1H)-subunit cyanamides;
1-{4-[(the 2-adamantyl is amino) (cyanoimino) methyl] phenyl } piperidines-4-formic acid;
N-(1-{4-[3-azabicyclo [3.2.2] ninth of the ten Heavenly Stems-3-base (cyanoimino) methyl] phenyl } tetramethyleneimine-3-yl)-N-methyl isophthalic acid-phenyl methanesulfonamide acid amides;
1-adamantyl { 4-[2-(1H-imidazoles-2-base sulfenyl) ethyl] piperidines-1-yl } methylene radical cyanamide;
N-2-adamantyl-N'-cyanic acid-4-(2-oxa--5-azabicyclo [2.2.1] heptan-5-yl) benzenyl amidine;
N-{4-[(cyanoimino) (1,3,3-trimethylammonium-6-azabicyclo [3.2.1] suffering-6-yl) methyl] benzyl }-1,1,1-three fluoro-N-sec.-propyl Toluidrins;
1-ethanoyl-N-(2-{5-[(cyanoimino) (1,3,3-trimethylammonium-6-azabicyclo [3.2.1] suffering-6-yl) methyl]-1H-benzoglyoxaline-1-yl } ethyl) piperidines-4-methane amide;
3-{4-[(cyanoimino) (1,3,3-trimethylammonium-6-azabicyclo [3.2.1] suffering-6-yl) methyl]-1H-indoles-1-yl } ethyl propionate;
N-1-adamantyl-N'-cyanic acid-1-(thiophene-2-base alkylsulfonyl) piperidines-4-carbonamidine;
N'-cyanic acid-4-(2,4 dichloro benzene oxygen base)-N-[4-(methylol)-2-adamantyl] fourth amidine;
4-[(5-chloro-pyridine-2-yl) oxygen base]-N'-cyanic acid-N-[4-(methylol) cyclohexyl]-N-methylbenzene carbonamidine;
N-2-adamantyl-N'-cyanic acid-2-[cyclohexyl (methyl) amino] ethanamidine;
N-2-adamantyl-N'-cyanic acid-1-methyl-5-(2-phenyl ethoxy)-1H-pyrazoles-4-carbonamidine;
2,4-two chloro-N-[1-([5-{ (cyanoimino) [(5-hydroxyl-2-adamantyl) amino] methyl }-4-(cyclopentyl sulfenyl) different azoles-3-yl] the oxygen base } methyl) cyclopropyl] BM;
Carboxylamine 4-[((cyanoimino) { 1-[3-cyanic acid-3-methyl but-1-ene base]-5-isobutoxy-1H-pyrazoles-4-yl } methyl) amino]-1-adamantane esters;
2-(5-hydroxyl-2-adamantyl)-3-oxo-2,3-dihydro-1H-isoindole-1-subunit cyanamide and 2-(6-hydroxyl-2-adamantyl)-3-oxo-2,3-dihydro-1H-isoindole-1-subunit cyanamide;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-4-[(pyridine-2-base alkylsulfonyl) methoxyl group] benzenyl amidine;
N'-cyanic acid-3-(cyclohexyl methoxyl group)-N-[5-(methylol)-2-adamantyl] benzenyl amidine;
N'-cyanic acid-N-(3-hydroxyl-1-adamantyl)-4-[(methyl sulphonyl) methoxyl group] benzenyl amidine;
N'-cyanic acid-N-(5-hydroxyl-2-adamantyl)-N-methyl-3-(2-phenyl ethoxy) benzenyl amidine; With
(3-hydroxyl-8-azabicyclo [3.2.1] suffering-8-yl) (9-methyl-9H-carbazole-3-yl) methylene radical cyanamide; With
1-(4-{ [2-(4-chlorophenoxy) phenyl] amino } piperidines-1-yl) the ethylidene cyanamide.
14. the method for treatment or prophylactic treatment illness in the Mammals of needs, this method comprises: the compound that gives claim 1 or claim 13.
15. the method for claim 14, wherein illness is selected from: Cushing's syndromes, non-insulin-dependent type ii diabetes, insulin resistant, obesity, lipid metabolism disorders; The metabolic syndromes, hyperglycemia, low glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia; Low HDL levels, high LDL level, atherosclerosis and its sequela, vascular restenosis, pancreatitis; Abdomen position obesity, retinopathy, ephrosis (nephropather), neuropathy, vascular hypertension; Osteoporosis, glaucoma, sacroiliitis, neuron dysfunction, neurodegeneration; The cognitive defect relevant with aging, dementia, alzheimer's disease, the cognitive function decline in alzheimer's disease and the relevant dementia is with the old and feeble cognitive defect relevant with neurodegeneration; Dementia, senile dementia, AIDS is dull-witted, anxiety, Phobias; Post-traumatic nervous sexual dysfunction, the acute mental disorder that steroidal causes, the cognitive defect relevant, general attention power defective illness, attention deficit superfunction illness (ADHD) with mellitus; Slight cognitive defect, the cognitive function decline in the Cushing's syndromes, schizophrenia, melancholia, severe depression illness; Psychotic depression, the melancholia in the Cushing's syndromes, intractable melancholia, the acute mental disorder that steroidal causes, and other disease relevant with hydrocortisone or glucocorticosteroid.
16. the method for claim 14, wherein illness is the non-insulin-dependent type ii diabetes.
17. the method for claim 14, wherein illness is an alzheimer's disease.
18. the method for claim 14, wherein illness is a melancholia.
19. the method for claim 14, wherein illness is a schizophrenia.
20. the method for claim 14, wherein illness is a hyperlipemia.
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